Amidino compounds, their manufacture and method of treatment

ABSTRACT

The invention relates to the compounds of the formula ##STR1##

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.07/978,004 filed Nov. 18, 1992, now pending which is acontinuation-in-part of application Ser. No. 07/960,211 filed Oct. 13,1992, now abandoned, which is a continuation of application Ser. No.07/714,108 filed Jun. 11, 1991, now abandoned.

SUMMARY OF THE INVENTION

The invention relates to the amidinophenoxyalkoxyphenyl derivatives andthio analogs as defined herein which are particularly useful asselective Leukotriene B₄ (LTB₄) receptor antagonists, methods forpreparation thereof, pharmaceutical compositions comprising saidcompounds, and a method of antagonizing LTB-4 and of treating conditionsor syndromes in mammals which are responsive to LTB-4 antagonism usingsaid compounds or pharmaceutical compositions comprising said compoundsof the invention.

Leukotriene B₄ (LTB₄) is an important inflammatory mediator being apotent chemotactic agent and activator of polymorphonuclear leucocytes(PMN's) and monocytes. It modulates the production and effects of otherimportant inflammatory mediators e.g. Interleukin-1 and gammainterferon. LTB₄ has been implicated in the pathogenesis of a number ofinflammatory diseases, such as rheumatoid arthritis, inflammatory boweldisease, psoriasis, non-steroidal-antiinflammatory-drug-inducedgastropathy, adult respiratory distress syndrome (ARDS), myocardialinfarction, allergic rhinitis, hemodialysis-induced neutropenia, andlate phase asthma.

The compounds of the invention are useful for the treatment of theconditions mediated by LTB₄ which are cited above. In addition, thecompounds are also useful for the treatment of pain and osteoarthritis,for the treatment of ocular conditions, such as ocular allergy andinflammation, and also for the treatment of dermatitis, such as atopicand contact dermatitis.

There is a strong need in the an in finding potent antagonists of LTB₄on human PMN's, especially those which are orally active. It has beenfound that the compounds according to the present invention exhibitsignificant LTB₄ antagonistic activity on human PMN's and are orallyactive.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to amidinophenoxyalkoxyphenyl derivatives and thioanalogs of the formula ##STR2## wherein the C(═NH)-NHR₃ group may be intautomeric or isomeric form; and pharmaceutically acceptable saltsthereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom an aliphatic hydrocarbon radical, an araliphatic hydrocarbonradical, an aromatic radical, and a cycloaliphatic hydrocarbon radical,or is amino which is disubstituted by a divalent aliphatic hydrocarbonradical or a said radical interrupted by oxygen;

R₂ is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbonradical, or is hydroxy which is etherified by an aliphatic alcohol,araliphatic alcohol, or aromatic alcohol or which is esterified by analiphatic or araliphatic carboxylic acid; or R₂ is hydroxy;

R₃ is hydrogen or an acyl radical which is derived from an organiccarbonic acid, an organic carboxylic acid, a sulfonic acid, or acarbamic acid;

X₁ and X₃, independently of one another, are oxygen (--O--) or sulphur(--S--); and

X₂ is a divalent aliphatic hydrocarbon radical which may be interruptedby an aromatic radical;

wherein the phenyl rings of formula I may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid;

wherein aryl in the above definitions may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid;

wherein a cycloaliphatic hydrocarbon radical may be substituted by analiphatic radical; which are particularly useful as selective LTB-4antagonists, methods for preparation thereof, pharmaceuticalcompositions comprising said compounds, and a method of antagonizingLTB-4 and of treating diseases in mammals which are responsive to LTB-4antagonism using said compounds or pharmaceutical compositionscomprising said compounds of the invention.

The compounds of the invention wherein the C(═NH)--NHR₃ group is intautomeric or isomeric form are represented by formula I' ##STR3##wherein R₁, R₂, R₃, X₁, X₂ and X₃ have meaning as defined for formula I.

As compounds according to the invention have a basic center, they canthus form acid addition salts, especially pharmaceutically acceptablesalts. These are formed, for example, with inorganic acids, such asmineral acids, for example sulfuric acid, a phosphoric or hydrohalicacid, or with organic carboxylic acids, such as (C₁ -C₄-)alkanecarboxylic acids which, for example, are unsubstituted orsubstituted by halogen, for example acetic acid, such as saturated orunsaturated dicarboxylic acids, for example oxalic, malonic, succinic,maleic, fumaric, phthalic or terephthalic acid, such ashydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic,tartaric or citric acid, such as amino acids, for example aspartic orglutamic acid, benzoic acid or with organic sulfonic acids, such as (C₁-C₄ -)alkane- or arylsulfonic acids which are unsubstituted orsubstituted, for example, by halogen, for example methane- ortoluenesulfonic acid. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

The general definitions used below have, if not defined differently, thefollowing meanings:

An aliphatic hydrocarbon radical is, for example, lower alkyl, loweralkenyl and secondarily lower alkynyl.

An araliphatic hydrocarbon radical is, for example, optionallysubstituted phenyl-lower alkyl and secondarily phenyl-lower alkenyl andphenyl-lower alkynyl.

A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl andsecondarily cycloalkenyl, which is unsubstituted or mono- orpolysubstituted, for example, disubstituted, by lower alkyl.

A divalent aliphatic hydrocarbon radical is, for example, loweralkylene.

A divalent aliphatic radical interrupted by oxygen is, for example,lower alkylene interrupted by oxygen, e.g. ethylene-O-ethylene.

A divalent aliphatic hydrocarbon radical which is interrupted by anaromatic radical is, for example, lower alkylene-phenylene-loweralkylene or lower alkylene-naphthylene-lower alkylene.

An aliphatic alcohol is, for example, a lower alkanol or lower alkenol,and an araliphatic alcohol is, for example, a phenyl-lower alkanol.

An aromatic alcohol is, for example, a phenol which is unsubstituted oris further substituted such as monosubstituted, for example,disubstituted or secondarily trisubstituted.

Hydroxy which is etherified by an aliphatic or araliphatic alcohol is,for example, lower alkoxy or lower alkenyloxy and phenyl-lower alkoxy.

An aliphatic carboxylic acid is, for example, a lower alkanoic or loweralkenoic acid, and an araliphatic carboxylic acid is, for example, aphenyl-lower alkanoic acid.

Hydroxy which is esterified by an aliphatic or araliphatic carboxylicacid is, for example, lower alkanoyloxy, secondarily lower alkenoyloxy,or isophenyl-lower alkanoyloxy.

An acyl radical which is derived from an organic carboxylic acid is, forexample, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted orsubstituted aroyl, such as benzoyl, naphthoyl, indanoyl or fluorenoyl,or heteroaroyl such as pyridylcarbonyl, thienylcarbonyl,pyrrolylcarbonyl, furanylcarbonyl, and imidazolylcarbonyl.

An acyl radical which is derived from an organic carbonic acid is, forexample, alkoxycarbonyl or alkenyloxycarbonyl which in each case areunsubstituted or substituted by an aromatic radical or iscycloalkoxycarbonyl which unsubstituted or substituted by lower alkyl.

An acyl radical which is derived from a sulfonic acid is, for example,alkanesulfonyl, arylalkanesulfonyl, cycloalkanesulfonyl or arylsulfonyl.

An acyl radical which is derived from a carbamic acid is, for example,amino-carbonyl which is substituted by alkyl, arylalkyl or aryl.

An aromatic radical is, for example, unsubstituted or substituted suchas monosubstituted or polysubstituted, for example, disubstituted orsecondarily trisubstituted carbocyclic aryl, such as phenyl, naphthyl,indanyl or fluorenyl, or heterocyclic aryl, such as pyridyl, thienyl,pyrrolyl, furanyl, and imidazolyl.

Aryl represents preferably monocarbocyclic aryl, advantageouslyoptionally substituted phenyl, such being phenyl or phenyl substitutedby e.g. lower alkyl, lower alkoxy, halogen or trifluoromethyl.

The phenyl rings of formulae I and IA as well as aromatic radicalsreferred to before and hereafter are generally unsubstituted or furthersubstituted such as monosubstituted or polysubstituted, for exampledisubstituted or secondarily trisubstituted, in particular, for example,by a substituent selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy,lower alkenoyloxy, and phenyl-lower alkanoyloxy. Preferably, the phenylrings of formula I and IA do not exhibit any additional substituent.

Preferred positions of the following structural elements in thecorresponding phenyl ring in formula I are: positions 4 (para) or 5(meta) for --CO--R₁, position 2 (ortho) or 3 (meta) for R₂, and position4 (para) for --C(═NH)--NHR₃. The substituent R₃ may be located on eithernitrogen of the --C(═NH)NH₂ grouping and both tautomeric or isomericforms are encompassed by the instant invention.

The term "substituted by one or more substituents" refers preferably toone, two or three such substituents, advantageously one or two.

The expression "lower" means that corresponding groups and compounds ineach case contain in particular not more than 7, preferably not morethan 4, carbon atoms.

Halogen is, in particular, fluorine, chlorine or bromine, andfurthermore includes iodine.

Lower alkyl is, in particular, C₁ -C₇ -alkyl and is, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl and furthermore includes corresponding pentyl, hexyl andheptyl radicals. C₁ -C₄ -Alkyl is preferred.

Lower alkenyl is, in particular, C₃ -C₇ -alkenyl and is, for example,2-propenyl or 1-, 2- or 3-butenyl. C₃ -C₅ -Alkenyl is preferred.

Lower alkynyl is, in particular, C₃ -C₇ -alkynyl and is preferablypropargyl.

Phenyl-lower alkyl is, in particular, phenyl-C₁ -C₄ -alkyl and ispreferably benzyl, 1- and 2-phenethyl, while phenyl-lower alkenyl andphenyl-lower alkynyl are, in particular, phenyl-C₂ -C₅ alkenyland-alkynyl, in particular 2-phenyl-vinyl, 3-phenylallyl and3-phenylpropargyl.

Cycloalkyl is, in particular, C₃ -C₇ -cycloalkyl and is, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, in particular, C₃ -C₇ -cycloalkenyl and is preferablycyclopent-2- or -3-enyl, or cyclohex-2- and -3-en-yl.

Lower alkylene e.g. in amino which is disubstituted by lower alkyleneis, in particular, C₂ -C₆ -alkylene and is, for example, butylene,pentylene, or 2,6-butylene. Preferred is C₄ -C₅ -alkylene, especiallypentylene.

Lower alkylene X₂ is, in particular, C₂ -C₈ -alkylene, preferablystraight-chain, and is, for example, ethylene, propylene, butylene,pentylene, hexylene, heptylene and also octylene. C₄ -C₇ -Alkylene ispreferred, especially pentylene and also butylene, hexylene orheptylene.

Lower alkylene which is interrupted by a phenyl radical (X₂) is, inparticular, lower alkylene-phenylene-lower alkylene or loweralkylene-naphthylene-lower alkylene such as C₂ -C₄-alkylene-phenylene-C₂ -C₄ -alkylene or C₂ -C₄ -alkylene-naphthylene-C₂-C₄ -alkylene, preferably straight-chain, and is, for example,methylene-phenylene-methylene, 1,2-ethylene-phenylene-1,2-ethylene, suchas 1,2-ethylene-1,4-phenylene-1,2-ethylene,1,3-propylene-phenylene-1,3-propylene, such as1,3-propylene-1,4-phenylene-1,3-propylene, orbutylene-phenylene-butylene radicals, also a corresponding1,2-ethylene-naphthylene-1,2-ethylene radical. C₂ -C₄-alkylene-phenylene-C₂ -C₄ -alkylene or C₂ -C₃ -alkylenenaphthylene-C₂-C₃ -alkylene is preferred, especially1,2-ethylene-1,4-phenylene-1,2-ethylene. Lower alkoxy is, in particular,C₁ -C₇ -alkoxy and is, for example, methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy, isobutyloxy, secobutyloxy, tert-butyloxy andfurthermore includes corresponding pentyloxy, hexyloxy and heptyloxyradicals. C₁ -C₄ -Alkoxy is preferred.

Lower alkenyloxy is, in particular, C₃ -C₇ -alkenyloxy and is, forexample, allyloxy or but-2-en- or but-3-enyloxy. C₃ -C₅ -Alkenyloxy ispreferred.

Phenyl-lower alkoxy is, in particular, phenyl-C₁ -C₄ -alkoxy, such asbenzyloxy, 1- or 2-phenylethoxy, 1-, 2- or 3-phenylpropyloxy.

Lower alkanoyloxy is, in particular, C₂ -C₈ -alkanoyloxy, in particular,C₂ -C₅ -alkanoyloxy, such as acetyloxy, propionyloxy or pivaloyoxy.

Lower alkenoyloxy is, in particular, C₃ -C₈ -alkenoyloxy, in particular,C₃ -C₅ -alkenoyloxy, such as propenoyloxy.

Phenyl-lower alkanoyloxy is, in particular, phenyl-C₂ -C₅ -alkanoyloxy,in particular, phenyl-C₂ -C₅ -alkanoyloxy, such as phenylacetyloxy,phenylpropionyloxy or phenylpivaloyloxy.

Alkoxycarbonyl is, in particular, C₂ -C₁₂ -alkoxycarbonyl and is, forexample, methoxy-, ethoxy-, propyloxy- pivaloyloxy- oroctyloxy-carbonyl. C₂ -C₉ -Alkoxycarbonyl is preferred.

Alkenyloxycarbonyl is, in particular, C₃ -C₁₂ -alkenyloxycarbonyl, forexample, allyloxycarbonyl. Preferred is C₃ -C₅ -alkenyloxycarbonyl.

Cycloalkyloxycarbonyl is, in particular, C₃ -C₇ -cycloalkoxycarbonyl,preferred is cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

Alkanesulfonyl is, in particular, C₁ -C₇ alkanesulfonyl and is, forexample, methane-, ethane-, n-propane- or isopropanesulfonyl. C₁ -C₄-Alkanesulfonyl is preferred.

Arylalkanesulfonyl is, in particular, phenyl-C₁ -C₇ alkanesulfonyl, forexample, benzyl- or 1- or 2-phenylethan-sulfonyl. Phenyl-C₁ -C₄-alkane-sulfonyl is preferred.

Cycloalkanesulfonyl is, in particular, C₃ -C₇ -cycloalkanesulfonyl,preferred is cyclopentanesulfonyl or cyclohexanesulfonyl.

Naphthyl is 1- or 2-naphthyl.

Indanyl is, for example, 1-, 2-, 3- or 4-indanyl.

Fluorenyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenyl.

Lower alkanoyl is, in particular, C₁ -C₇ -alkanoyl and is, for example,formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C₂ -C₅-Alkanoyl is preferred.

Phenyl-lower alkanoyl is, in particular, phenyl-C₂ -C₇ -alkanoyl and is,for example, phenylacetyl or 2- or 3-phenylpropionyl. Phenyl-C₂ -C₄-alkanoyl is preferred.

Substituted aroyl represents aroyl, such as benzoyl, which issubstituted e.g. by lower alkoxy, lower alkyl, hydroxy, hydroxymethyl orby acyloxymethyl (such as lower alkanoyloxymethyl or benzoyloxymethyl.

Naphthoyl is 1- or 2-naphthoyl.

Indanoyl is, for example, 1-, 2-, 3- or 4-indanoyl.

Fluorenoyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenoyl.

Esterified carboxyl represents preferably lower alkoxycarbonyl oraryl-lower alkoxycarbonyl.

Amidated carboxyl represents preferably aminocarbonyl, mono- or di-loweralkylaminocarbonyl, (mono-aryl-mono-lower alkyl)aminocarbonyl, mono- ordi-(aryl-lower alkyl)aminocarbonyl or (mono-aryl-lower alkyl-mono-loweralkyl)aminocarbonyl.

The compounds of the invention exhibit valuable pharmacologicalproperties in mammals, and are particularly useful as selectiveLeukotriene B₄ (LTB₄) receptor antagonists, e.g. for the treatment of acondition or syndrome in a mammal responsive to the selective antagonismof LTB₄ receptors, such as rheumatoid arthritis, inflammatory boweldisease, psoriasis, non-steroidal-antiinflammatory-drug-inducedgastropathy, adult respiratory distress syndrome (ARDS), myocardialinfarction, allergic rhinitis, hemodialysis-induced neutropenia, andlate phase asthma. The compounds of the invention are also useful asanalgesics for the treatment of pain of any origin, and for thetreatment of osteoarthritis, also for the treatment of ocularconditions, such as ocular allergy and inflammation, and also for thetreatment of dermatitis, e.g. atopic and contact dermatitis.

The above-cited properties are demonstrable in in vitro and in vivotests, using advantageously mammals, e.g. rats. Said compounds can beapplied in vitro in the form of solutions, e.g. preferably aqueoussolutions, and in vivo either enterally or parenterally, advantageouslyorally, e.g. as a suspension or in aqueous solution. The dosage in vitromay range between about 0.5 ng/ml and about 100 ng/ml. The dosage invivo may range, depending on the route of administration, between about1 and about 1000 mg/kg per day.

Beneficial effects are evaluated in pharmacological tests generallyknown in the art, e.g. as illustrated herein.

Receptor Binding with [3H]-LTB₄ to Intact Human Neutrophils:

Neutrophils (PMN's) are prepared from uncoagulated human venous blood.Blood is dispersed into 50 ml polypropylene tubes containing 15 ml ofHESPAN (Dupont, Wilmington, Del.), and mixed. Tubes are allowed to standat room temperature for 40 minutes until most of the red blood cellssediment. The supernatants are removed and centrifuged for 5-10 min at400×g. The remaining pellets are diluted in 70 ml of Phosphate BufferedSaline without calcium and magnesium (PBS without metals; GIBCO, GrandIsland, N.Y.) and 35 ml of this suspension are placed in each of twopolypropylene tubes containing 15 ml of Ficoll-Paque (Sigma, St. Louis,Mo.). Gradients are then centrifuged for 15 minutes at 420×g. Themononuclear cell layer is discarded and the remaining red blood cellpellet is resuspended in 10 ml of PBS without metals. Twenty ml offiltered deionized water are added to the suspension for approximately20 see followed by the same volume of buffer at two times the normalconcentration. The cell suspension is mixed and centrifuged for 5 min at200×g, followed by one wash with buffer, and final resuspension.

Binding of [³ H]LTB₄ to LTB₄ receptors is measured in intact humanpolymorphonuclear leukocytes, as described by Gorman and Lin (Gorman, R.and Lin, A Methods Enzymol. 141: 372-378, 1987). Intact humanneutrophils are suspended in Hank's Balanced Salt Solution (HBSS) at aconcentration of 3×106 cells/assay tube. An aliquot of the cellsuspension (300 μl) is added to triplicate tubes containing 50 μl[3H]LTB₄ (specific activity 32 Ci/mmol, DuPont-NEN, Boston, Mass.) at afinal concentration of 0.5 nM, 100 μl buffer and 50 μl drug or buffer.Nonspecific binding is determined in the presence of 300 nM LTB₄. Thereaction is initiated by addition of cell suspension and continued at 0°C. for 20 min. Bound radioactivity is isolated by vacuum filtrationthrough Whatman GF/C glass fiber filters using a Brandel cell harvesterand unbound radioactivity removed with 2×5 ml washes with ice-coldsaline. Filters are placed in polyethylene scintillation mini-vials towhich is added 3.5 ml of Formula-989 scintillation cocktail (NEN). Afterequilibration, radioactivity determinations and data calculations areperformed using non-linear regression analysis on RS/1.

LTB₄ -Induced PMN Aggregation

Human PMNs are prepared as previously described. Neutrophil aggregationis assessed by monitoring the intensity of light passing through asuspension of cells (Craddock et at., J. Clin. Invest. 60: 260-264,1977) using a Payton dual channel aggregometer (model 300BD). Cuvettescontaining 0.25 ml of cell suspension (25×106 cells/ml) in PBS withoutcalcium and magnesium are incubated with 5 μg/ml ml of cytochalasin Bfor 2 minutes at 37° C. 5 μl of 2 μM LTB₄ in PBS (20 nM finalconcentration) are added and the aggregation response monitored for 3-5min, the time required for optimal response, Compounds are solubilizedin 0.01M DMSO and then diluted in PBS to 0.001 M. 5 μl of compoundsolution is added along with cytochalasin B and cells as describedabove. Following the preincubation period 5 μl of 2 μM LTB₄ are addedand aggregation is measured. Percent inhibition of aggregation iscalculated by comparing peak heights in the presence and absence ofcompound. Percent inhibition is plotted as a function of the logconcentration of compound and the IC₅₀ determined directly from thegraph.

LTB₄ -Induced Neutropenia in the Rat

Male Sprague Dawley rats (crl: CDBR; Charles River, Wilmington, Mass.)(250-300 grams) are fasted overnight prior to the experiment. At leastsix animals are used per treatment group. Rats are given vehicle orcompound either intravenously or orally and at intervals after dosing,neutrophil counts are determined from blood samples obtained just priorto and 20 seconds after intravenous infusion of 200 ng LTB₄. In studieswhere compound is administered orally, drug is given by gavage. Whendrug is administered intravenously, rats are first anesthetized with 50mg/kg i.p. of Sodium Pentabarbital. The jugular vein is exposed andcleaned of the surrounding tissue. At 3, 4 or 18 hours followingadministration of compound or vehicle by either route, blood samples aretaken (0.3 ml of blood in 1.5 ml polypropylene microcentrifuge tubecontaining 0.01 ml 7.5% EDTA). Blood neutrophil counts are determinedusing a Technicon H-1 hematology instrument. Antagonism of the LTB₄-induced neutropenia response for the compounds tested is calculated.

Analgesic activity can be demonstrated e.g. in the Randall-Selitto testfor analgesia, e.g. as described in Arch. Int. Pharmacodyn. Ther. 111,409 (1957).

Antiinflammatory activity can be demonstrated by measuring theinhibition of the edema and inhibition of the influx ofpolymorphonuclear (PMN's) and mononuclear leukocytes (monocytes andmacrophages) after oral administration in the rat model in whichpleurisy is first induced by injecting carrageenin into the pleuralcavity, e.g. according to A. P. Almeida et al., J. Pharmacol. Exp.Therap. 214, 74 (1980), in particular during the late phase of thecarrageenin-induced pleurisy.

Bronchial effects such as anti-asthmatic activity, can be demonstratedin the antigen-induced guinea pig bronchoconstriction test, e.g. asdescribed by Anderson et al, Br. J. Pharmacol. 1983, 78, 67-74.

The trinitrobenzenesulfonic acid-induced chronic colitis test in therat, e.g. as described by Wallace et al, Gastroenterology 1989, 96,29-36, can be used to evaluate compounds for effects indicative ofutility in inflammatory bowel diseases.

The arachidonic acid-induced mouse ear edema test, e.g. as described byYoung et al, J. Invest, Dermatol. 1984., 82, 367-371 can be used toevaluate compounds for effects indicative of utility in dermatologicaldisorders such as psoriasis.

The invention especially relates to compounds of formula I andpharmaceutically acceptable salts thereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl,phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, naphthyl, indanyl,fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and cycloalkenyleach being unsubstituted or mono- or polysubstituted by lower alkyl, oris amino which is disubstituted by lower alkylene;

R₂ is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkenyl,lower alkynyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy,phenoxy, lower alkanoyloxy, lower alkenoyloxy, or phenyl-loweralkanoyloxy; or R₂ is hydroxy;

R₃ is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which isunsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl,or is cycloalkoxycarbonyl being C₁ -C₇ alkanesulfonyl, phenyl-C₁ -C₇alkanesulfonyl, C₃ -C₇ -cycloalkanesulfonyl, or unsubstituted or mono-or polysubstituted by lower alkyl, or is lower alkanoyl or phenyl-loweralkanoyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or isphenylsulfonyl, or is aminocarbonyl which is substituted by lower alkyl,phenyl-lower alkyl or phenyl;

X₁ and X₃, independently of one another, are O or S;

X₂ is lower alkylene, lower alkylene-phenylene-lower alkylene or loweralkylene-naphthylene-lower alkylene;

wherein the phenyl rings of formula I may be, independently of oneanother, substituted by one or more substituents selected from halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy,lower alkenoyloxy and phenyl-lower alkanoyloxy;

wherein the aromatic radicals in the above definitions may be,independently of one another, substituted by one or more substituentsselected from halogen, trifluoromethyl, lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-loweralkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-loweralkanoyloxy.

The invention especially relates to compounds of formula I andpharmaceutically acceptable salts thereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom C₁ -C₇ -alkyl, phenyl-C₁ -C₇ -alkyl, phenyl and C₃ -C₆ -cycloalkyl,C₃ -C₆ -cycloalkyl being unsubstituted or mono- or polysubstituted by C₁-C₇ -alkyl, or is amino which is disubstituted by C₃ -C₆ -alkylene;

R₂ is hydrogen, C₁ -C₇ -alkoxy or phenyl-C₁ -C₄ -alkoxy; or R₂ ishydroxy;

R₃ is hydrogen, C₁ -C₂ -alkoxy-carbonyl, C₂ -C₅ -alkanoyl, phenyl-C₂ -C₅-alkanoyl, benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁ -C₇ -alkyl, or C₁ -C₇ -alkoxy, C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₇-alkyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is C₁ -C₇alkanesulfonyl, phenyl-C₁ -C₇ alkanesulfonyl, C₃ -C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which issubstituted by C₁ -C₇ -alkyl, phenyl-C₁ -C₇ -alkyl or phenyl;

X₁ and X₃ each are --O--, or furthermore are, independently of oneanother, --O-- or --S--;

X₂ is C₂ -C₇ -alkylene or C₂ -C₄ -alkylene-phenylene-C₂ -C₄ -alkylene;

wherein the phenyl rings of formula I may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁ -C₇ -alkyl, andC₁ -C₇ -alkoxy;

wherein phenyl in the above definitions is unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁ -C₇ -alkyl, andC₁ -C₇ -alkoxy.

The invention especially relates to compounds of formula I andpharmaceutically acceptable salts thereof, in which --CO--R₁ is locatedin position 4 (para) or 3 or 5 (meta) of the corresponding phenyl ringwith respect to --X₁ --; R₂ -- is located in position 2 (ortho) or 3(meta) of the corresponding phenyl ring with respect to --X₁ --; and--C(═NH)--NHR₃ is located in position 4 (para) of the correspondingphenyl ring with respect to --X₃ --.

The invention especially relates to compounds of formula IA ##STR4##wherein the C(═NH)--NHR₃ group may be in tautomeric or isomeric form,and pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -₄ -alkylamino, such as di-ethylamino or di-isopropylamino,C₁ -C₄ alkyl-phenylamino, such as phenyl-isopropyl-amino, C₁ -C₄alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, such as methyl-benzyl-amino, di-C₃-C₆ -cycloalkylamino, such as di-cyclohexylamino, which is unsubstitutedor substituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy; or R₂ is hydroxy;

R₃ is hydrogen, C₁ -C₁₂ -alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁ -C₄ -alkoxycarbonyl, such asbenzyloxycarbonyl, C₂ -C₅ -alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁ -C₄ -alkylor by C₁ -C₄ -alkoxy, such as 3,4-dimethoxybenzoyl, C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₄-alkyl, such as 2-isopropyl-5 -methyl-cyclohexylcarbonyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene;

wherein the phenyl rings of formula IA may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁ -C₄ -alkyl, andC₁ -C₄ -alkoxy.

The invention especially relates to compounds of formula IA andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino,C₁ -C₄ -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C₁ -C₄-alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, such as methyl-benzyl-amino, di-C₃-C₆ -cycloalkylamino, such as di-cyclohexylamino which is unsubstitutedor substituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy; or R₂ is hydroxy;

R₃ is C₁ -C₄ alkanesulfonyl, such as methane-, ethane- orisopropanesulfonyl, phenyl-C₁ -C₄ -alkanesulfonyl, such asbenzylsulfonyl, C₃ -C₇ -cycloalkane-sulfonyl, such ascyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which issubstituted by C₁ -C₄ -alkyl, phenyl-C₁ -C₄ -alkyl or phenyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene.

The invention especially relates to compounds of formula IA andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino,C₁ -C₄ -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C₁ -C₄-alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, such as methyl-benzyl-amino, di-C₃-C₆ -cycloalkylamino, such as di-cyclohexylamino which is unsubstitutedor substituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy; or R₂ is hydroxy;

R₃ is hydrogen; or R₃ is lower alkanoyl, such as acetyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene.

The invention further especially relates to compounds of formula IA andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-isopropylamino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy;

R₃ is C₁ -C₁₂ -alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁ -C₄ -alkoxycarbonyl, such asbenzyloxycarbonyl, C₂ -C₅ -alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁ -C₄ -alkyl,or C₁ -C₄ -alkoxy, such as 3,4-dimethoxybenzoyl, C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₄-alkyl, such as 2-isopropyl-5 -methyl-cyclohexylcarbonyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, especially pentylene.

The invention further especially relates to compounds of formula IA andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy;

R₃ is hydrogen or C₁ -C₄ -alkanoyl, such as acetyl;

X₁ and X₃ are --O--;

X₁ is C₄ -C₇ -alkylene, especially pentylene.

The invention also particularly relates to the compounds of formula IB##STR5## wherein the C(═NH)--NHR₃ group may be in tautomeric or isomericform, and pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino,C₁ -C₄ alkyl-(phenyl)amino, such as phenyl-isopropyl-amino, C₁ -C₄-alkyl-(phenyl-C₁ -C₄ -alkyl )-amino, such as methyl-benzyl-amino, di-C₃-C₆ -cycloalkylamino, such as di-cyclohexylamino, which is unsubstitutedor substituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy; or R₂ is hydroxy;

R₃ is hydrogen, C₁ -C₁₂ -alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁ -C₄ -alkoxycarbonyl, such asbenzyloxycarbonyl, C₂ -C₅ -alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁ -C₄ -alkyl,or C₁ -C₄ -alkoxy, such as 3,4-dimethoxybenzoyl, C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₄-alkyl, such as 2-isopropyl-5 -methyl-cyclohexylcarbonyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene;

wherein the phenyl tings of formula IB may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁ -C₄ -alkyl, andC₁ -C₄ -alkoxy.

The invention especially relates to compounds of formula IB andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino,

C₁ -C₄ -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino,

C₁ -C₄ alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, such as methyl-benzyl-amino,di-C₃ -C₆ -cycloalkylamino, such as di-cyclohexylamino, which isunsubstituted or substituted by C₁ -C₄ -alkyl, or 1-piperidinosubstituted by C₁ -C₄ -alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen or C₁ -C₄ -alkoxy, such as methoxy; or R₂ is hydroxy;

R₃ is C₁ -C₄ alkanesulfonyl, such as methane-, ethane- orisopropanesulfonyl, phenyl-C₁ -C₄ -alkanesulfonyl, such asbenzylsulfonyl, C₃ -C₇ -cycloalkane-sulfonyl, such ascyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which issubstituted by C₁ -C₄ -alkyl, phenyl-C₁ -C₄ -alkyl or phenyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene.

The invention especially relates to compounds of formula IB andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino,C₁ -C₄ -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C₁ -C₄alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, such as methyl-benzyl-amino, di-C₃-C₆ -cycloalkylamino, such as di-cyclohexylamino, which is unsubstitutedor substituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen, hydroxy or C₁ -C₄ -alkoxy, such as methoxy;

R₃ is hydrogen; or R₃ is C₂ -C₅ -alkanoyl, such as acetyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, such as pentylene.

The invention further especially relates to compounds of formula IB andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁ -C₄ -alkylamino, such as di-ethylamino or di-isopropylamino;

R₂ is hydrogen, hydroxy or C₁ -C₄ -alkoxy, such as methoxy;

R₃ is hydrogen or C₂ -C₅ -alkanoyl, such as acetyl;

X₁ and X₃ are --O--;

X₂ is C₄ -C₇ -alkylene, especially pentylene.

The invention relates in particular to the novel compounds itemized inthe examples and to the manners of preparation described therein.

The invention further relates to methods for the preparation of thecompounds according to the invention. The preparation of compounds ofthe formula I is, for example, characterized in that,

a) a compound of the formula IIa ##STR6## or a salt thereof in which Z₁is a radical which can be convened into the variable --CO--R₁, Z₁ isconvened into the variable --CO--R₁, or,

b) for the manufacture of compounds of the formula I in which R₃ ishydrogen, in a compound of the formula IIIa ##STR7## or a salt thereofin which Z₂ is a radical which can be convened into the variable--C(═NH)--NH--R₃, Z₂ is convened into the variable--C(═NH)--NH--R₃, or

c) a compound of the formula IVa ##STR8## or a salt thereof is reactedwith a compound of the formula IVb ##STR9## or a salt thereof in whichZ₃ is a group of the formula --X₁ --X₂ --Z₅ and Z₄ is --Z₆, or Z₃ is--Z₆ and Z₄ is a group of the formula Z₅ --X₂ --X₃ --, wherein one ofthe radicals Z₅ and Z₆ is hydroxy or mercapto and the other is hydroxy,mercapto or reactive esterified hydroxy, and, if desired, a compound ofthe formula I or a salt thereof obtainable according to the process orin another manner is converted into another compound or a salt thereofaccording to the invention, a free compound of the formula I obtainableaccording to the process is convened into a salt, a salt obtainableaccording to the process is convened into the free compound of theformula I or into another salt, or a mixture of isomers obtainableaccording to the process is resolved and the desired compound isisolated.

Salts of starting materials which contain at least one basic centre, forexample of the formula IIa, are appropriate acid addition salts, whilesalts of starting materials which contain an acid group are present assalts with bases.

A radical Z₁ which can be converted into the variable --CO--R₁ is, forexample, cyano, carboxy or a salt or activated carboxy.

A radical Z₂ which can be converted into the variable --C(═NH)--NHR₃ is,for example, (lower) alkoxy-iminocarbonyl or halogeno-iminocarbonyl[Halogeno--C(═NH)--].

Reactive esterified hydroxy (e.g. Z₅ or Z₆) is, inparticular, hydroxyesterified with a strong inorganic acid or organic sulfonic acid, andis, for example, halogen, such as chlorine, bromine or iodine,sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, such as,fluorosulfonyloxy, (C₁ -C₇ -)alkanesulfonyloxy which, if desired, issubstituted, for example, by halogen, such as, methane- ortrifluoromethanesulfonyloxy, (C₅ -C₇ -)cycloalkanesulfonyloxy, such as,cyclohexanesulfonyloxy, or benzenesulfonyloxy which, if desired, issubstituted, for example by (C₁ -C₇ -)alkyl or halogen, such as,p-bromobenzene- or p-toluenesulfonyloxy.

The reactions described in the variants above and below are carried outin a manner known per se, for example in the absence or in the customarymanner in the presence of a suitable solvent or diluent or a mixturethereof, the reaction being carried out, according to need, withcooling, at room temperature or with warming, for example in atemperature range from about -80° C. up to the boiling point of thereaction medium, preferably from about -10° C. to about +180° C., and,if necessary, in a closed vessel, under pressure, in an inert gasatmosphere and/or under anhydrous conditions.

Process a):

A compound of the formula IIa in which Z₁ is activated carboxy (Z₁) is,for example, an anhydride thereof, including a mixed anhydride, such asan acid halide, for example chloride, or an anhydride with a formicester, an activated carboxylic ester such as cyanomethyl,(4-)nitrophenyl, polyhalogenophenyl, for example pentachlorophenyl,esters.

The reaction is, for example, carded out with an agent suitable tointroduce R₃, for example, an amine of the formula H--R₁. The reactionwith compounds of the formula IIa in which Z₁ carboxy or a salt thereof,for example, takes place under water-eliminating conditions, forexample, with azeotropic removal of the water of reaction, or bytreatment with a suitable condensing agent, for example,N,N'-dicyclohexyl-carbodiimide. The reaction with an activated carboxyderivative may advantageously be carried out in the presence of a base.

Suitable bases are, for example, alkali metal hydroxides, hydrides,amides, alkanolates, carbonates, triphenylmethylides, di(loweralkyl)amides, aminoalkylamides or lower alkyl silylamides, ornaphthaleneamines, lower alkylamines, basic heterocycles, ammoniumhydroxides, and also carbocyclic amines. Examples which may be mentionedare sodium hydroxide, sodium hydride, sodium amide, sodium (m)ethoxide,potassium tert-butoxide, potassium carbonate, lithiumtriphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)amide, potassiumbis(trimethylsilyl)amide,dimethylaminonaphthalene, di- or triethylamine, orethyldiisopropylamine, N-methylpiperidine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Preferably, those compounds of the formula IIa are employed in which Z₁is activated carboxy. The corresponding reaction is carried out using anamine of the formula H--R₁. Preferred compounds of the formula IIa arecorresponding acid halides such as acid chlorides or bromidesderivatives thereof.

Process b):

Alkoxy-iminocarbonyl is, for example C₁ -C₄ alkoxy-iminocarbonyl such asmethoxy- or ethoxy-iminocarbonyl, whereas halogeno-iminocarbonyl is, forexample chloro-iminocarbonyl.

Preferably, those compounds of the formula Ilia are employed in which Z₂is C₁ -C₄ alkoxy-iminocarbonyl such as methoxy- or ethoxy-iminocarbonyl.The reaction is preferably carried out by reacting with ammonia andusing an acid resulting in the corresponding acid addition salt of theproduct. As acids are used, for example, inorganic acids, such asmineral acids, for example sulfuric acid, a phosphoric or hydrohalicacid, or with organic carboxylic acids, such as (C₁ -C₄)alkanecarboxylicacids which, for example, are unsubstituted or substituted by halogen,for example acetic acid, such as saturated or unsaturated dicarboxylicacids, for example oxalic, malonic, succinic, maleic, fumaric, phthalicor terephthalic acid, such as hydroxycarboxylic acids, for exampleascorbic, glycolic, lactic, malic, tartaric or citric acid, such asamino acids, for example aspartic or glutamic acid, benzoic acid or withorganic sulfonic acids, such as (C₁ -C₄)alkane- or arylsulfonic acidswhich are unsubstituted or substituted, for example, by halogen, forexample methane- or toluenesulfonic acid. Preferred acids are hydrohalicacids, especially hydrochloric acid, organic sulfonic acids, especiallymethanesulfonic acid, or dicarboxylic acids, especially maleic acid.

Process c):

Preferably, those compounds of the formulae IVa and IVb are employed inwhich Z₃ is a group of the formula --X₁ --X₂ --Z₅, wherein Z₅ ishalogen, especially bromine, and Z₄ is hydroxy.

The reaction is carried out preferably in the presence of a base e.g. asmentioned above, such as cesium carbonate.

The starting material can be prepared following methods known per se.

In order to prepare the starting material of the formula IIa, forexample, a compound of the formula (IIb) ##STR10## in which Z₃preferably is a group of the formula --X₁ --X₂ --Z₅, wherein Z₅preferably is reactive esterified hydroxy, is reacted with a compound ofthe formula ##STR11## in which Z₄ is hydroxy or mercapto, following themethod as described in process c ).

If one of variables Z₃ and Z₅ represents reactive esterified hydroxy,the other preferably represents hydroxy or mercapto. A compound of theformula IVb can be obtained, for example, by convening Z₂ of a compoundof the formula ##STR12## in which Z₂ is a radical which can be convenedinto the variable --C(═NH)--NH--R₃ following the method as described inprocess b). Compounds of formulae (IIb) and (IIc) are known or can beprepared according to methods known per se.

Preferably, Z₃ is a group of the formula X₁ --X₂ --Z₅, wherein Z₅preferably is reactive esterified hydroxy, such as chlorine or bromine,and Z₄ is hydroxy or furthermore mercapto. A corresponding compound ofthe formula IIb can be obtained, for example, by reacting a compound ofthe formula Z₅ --X₂ --Z₅ (IId) with a compound of the formula ##STR13##preferably in the presence of a base.

In order to prepare the starting material of the formula IIIa, Z₁ of acompound of the formula (IIb) is convened into radical --CO--R₁following the method as described in process a) resulting in compound ofthe formula ##STR14## which, in the next step, is reacted with acompound of the formula (IIc) following the method as described inprocess c).

The starting materials and intermediates wherein R₂ is hydroxy areprepared from compounds wherein R₂ is e.g. methoxy by solvolysisthereof, e.g. with boron tribromide.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carded out, or the processis discontinued at any stage thereof, or in which the starting materialsare formed under the reaction conditions, or in which the reactioncomponents are used in the form of their salts or optically pureantipodes.

A compound according to the invention which is obtainable by the processcan be convened into another compound according to the invention in amanner known per se.

If one of the variables contains mono-substituted amino (for exampleR₁), corresponding compounds of the formula I or salts thereof can beN-alkylated in a manner known per se; likewise, N-mono-substitutedcarbamoyl (for example R₁) can further be N-alkylated. The(aryl-)alkylation is carried out, for example, using a reactive ester ofan (aryl-)C₁ -C₇ -alkyl halide, for example a bromide or iodide, an(aryl-)C₁ -C₇ -alkylsulfonate, for example a methanesulfonate orp-toluenesulfonate, or a di-C₁ -C₇ -alkyl sulfate, for example dimethylsulfate, preferably under basic conditions, such as in the presence ofsodium hydroxide solution or potassium hydroxide solution, andadvantageously in the presence of a phase-transfer catalyst, such astetrabutylammonium bromide or benzyltrimethylammonium chloride, where,however, stronger basic condensing agents, such as alkali metal amides,hydrides or alkoxides, for example sodium amide, sodium hydride orsodium ethoxide, may be necessary.

If R₃ is hydrogen, the corresponding amidino group can be N-acylatedaccordingly. The acylation is carried out in a manner known per se usinga suitable acylating agent. An example of a suitable acylating agent isa compound of the formula Ac--Z₇, where Ac denotes an acyl radicalcorresponding to the variable R₃, and Z₇ denotes in particular reactiveactivated hydroxyl. Appropriate hydroxyl can be activated, for example,by strong acids such as hydrohalic or carboxylic acid, for example byhydrochloric, hydrobromic acid, an optionally substituted, for exampleby halogen, alkanecarboxylic acid or by an acid of the formula Ac--OH,or by suitable activating or coupling reagents of the type detailedhereinafter, in particular in situ. Ac--Z₇ can furthermore represent anactivated ester, where Z₇ denotes, in particular, cyanomethoxy, phenoxy,(4-)nitrophenoxy or polyhalogeno-, such as pentachlorophenoxy.Activating and coupling reagents which can be employed are, inparticular, carbodiimides, for example N,N'-di-C₁ -C₄ -alkyl- orN,N'-di-C₅ -C₇ -cycloalkyl-carbodiimide, such as diisopropylcarbodiimideor N,N'-dicyclohexylcarbodiimide, advantageously with the addition of anactivating catalyst such as N-hydroxysuccinimide or optionallysubstituted, for example by halogen, C₁ -C₇ -alkyl or C₁ -C₇ -alkoxy,N-hydroxy-benzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide,furthermore C₁ -C₄ -alkyl halogenoformate, for example isobutylchloroformate, suitable carbonyl compounds, for exampleN,N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate or2-tert-butyl-5-methyl-isoxazolium perchlorate, suitable acylaminocompounds, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,or suitable phosphoryl cyanamides or azides, for examplediethylphosphoryl cyanamide or diphenylphosphoryl azide, furthermoretriphenylphosphine disulfide or 1-C₁ -C₄ -alkyl-2-halogeno-pyridiniumhalides, for example 1-methyl-2-chloropyridinium iodide. Z₇ preferablydenotes halogen such as chlorine or bromine, Ac--O--, and advantageouslyphenoxy.

If the compounds of the formula (I), (IA) or (IB) contain unsaturatedradicals, such as (lower)alkenyl groups, these can be converted intosaturated radicals in a manner known per se. Thus, for example, multiplebonds are hydrogenated by catalytic hydrogenation in the presence ofhydrogenation catalysts, suitable for this purpose being, for example,nickel, such as Raney nickel, and noble metals or their derivatives, forexample oxides, such as palladium or platinum oxide, which may beapplied, if desired, to support materials, for example to carbon orcalcium carbonate. The hydrogenation may preferably carried out atpressures between 1 and about 100 at and at room temperature betweenabout -80° to about 200° C., in particular between room temperature andabout 100° C. The reaction is advantageously carried out in a solvent,such as water, a lower alkanol, for example ethanol, isopropanol orn-butanol, an ether, for example dioxane, or a lower alkanecarboxylicacid, for example acetic acid.

The invention also relates to any novel starting materials and processesfor their manufacture and their use.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, optical isomers (antipodes), racemates, or mixtures thereof.The aforesaid possible isomers or mixtures thereof are within thepurview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysico-chemical differences of the constituents, into the puregeometric or optical isomers, diastereoisomers, racemates, for exampleby chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g. by separationof the diastereoisomers salts thereof, obtained with an optically activeacid or base, and liberating the optically active acidic or basiccompound. Racemic amidines (wherein R₃ represents hydrogen) can thus beresolved into their optical antipodes e.g. by fractional crystallizationof a salt formed with an optically active acid.

Finally, the compounds of the invention are either obtained in the freeform, or as a salt thereof.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to antagonize LTB₄ receptors,and for the treatment of a condition or syndrome responsive to theselective antagonism of LTB₄ receptors, comprising an effective amountof a pharmacologically active compound of the invention, alone or incombination, with one or more pharmaceutically acceptable carriers.

The novel pharmaceutical products contain, for example, from about 10%to about 80%, preferably from about 20% to about 60%, of the activecompound. Examples of pharmaceutical products according to the inventionfor enteral or parenteral administration are those in dose-unit formssuch as coated tablets, tablets, capsules or suppositories, as well asampoules. These are prepared in a manner known per se, for example usingconventional mixing, granulating, coating, dissolving or freeze-dryingprocesses. Thus, pharmaceutical products for oral use can be obtained bycombining the active compound with solid excipients, where appropriategranulating a mixture which is obtained, and processing the mixture orgranules, if desired or necessary, after addition of suitableauxiliaries to tablets or cores of coated tablets.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose andor polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. Cores of coated tablets are provided withsuitable, optionally enteric, coatings, using, inter alia, concentratedsugar solutions which optionally contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or solvent mixtures or,for the preparation of enteric coatings, solutions of suitable celluloseproducts such as acetyl cellulose phthalate orhydroxypropylmethylcellulose phthalate. Colorants or pigments can beadded to the tablets or coatings of coated tablets, for example, toidentify or to indicate various doses of active compound. In addition,they may also contain other therapeutically valuable substances. Saidcompositions are prepared according to conventional mixing, granulatingor coating methods, respectively, and contain about 0.1 to 75%,preferably about 1 to 50%, of the active ingredient.

Suitable formulations for topical application, e.g. to the skin andeyes, are preferably aqueous solutions, ointments, creams or gelswell-known in the art.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carder. Advantageous cardersinclude absorbable pharmacologically acceptable solvents to assistpassage through the skin of the host. Characteristically, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

In conjunction with another active ingredient, a compound of theinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The invention further particularly relates to a method for the treatmentof a condition or syndrome responsive to the selective antagonism ofLTB₄ receptors, such as rheumatoid arthritis, inflammatory boweldisease, psoriasis, non-steroidal-antiinflammatory-drug-inducedgastropathy, adult respiratory distress syndrome (ARDS), myocardialinfarction, allergic rhinitis, hemodialysis-induced neutropenia, andlate phase asthma; also for the treatment of osteoarthritis, of pain andof ocular allergies and inflammations; and also for the treatment ofatopic and contact dermatitis.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 70 kg may contain e.g. between about1 and about 1000 mg/kg per day of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg. The structure of final products, intermediates and startingmaterials are confirmed by standard analytical methods, e.g.microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR).Abbreviations used are those conventional in the art.

The compounds wherein R₃ is not hydrogen have been assigned the isomericstructure in which R₃ is located on the imino (C═N) nitrogen of theamidine group; however, such may also exist in the isomeric form inwhich R₃ is on the amino nitrogen of the amidine group.

EXAMPLE 1

A stirred, 0° C. solution of ethyl4-[5-[2-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(420 mg, 0.87 mmol) in 20 mL anhydrous ethanol is treated with anhydroushydrogen chloride gas for 5 minutes. After warming to room temperature,the resulting solution is concentrated in vacuo, redissolved inchloroform (20 mL) and reconcentrated. The resulting hydrochloride saltis then dissolved in ethanol (40 mL), transferred to a pressure tube andtreated with anhydrous ammonia for 10 minutes at 0° C. The pressure tubeis sealed and heated to 100° C. for 45 minutes. Upon cooling andconcentrating in vacuo, the resulting material is purified bychromatography on silica gel (15 g) with 3-20% methanol/dichloromethaneas the eluent to afford4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride as a colorless foam:

CHN calculated for C₂₆ H₃₈ N₃ O₄ Cl-1.0H₂ O; Theory: % C: 61.22; % H:7.91; % N: 8.24; Found: % C: 61.48; % H: 7.57; % N: 8.22. ##STR15##(i-Prop=isopropyl)

The starting material, ethyl4-[5-[2-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate,can be prepared, for example, as follows:

A stirred, 0° C. solution of 4-hydroxybenzonitrile (50.7 g, 426 mmol) in1400 mL of dichloromethane and 75 mL anhydrous ethanol is treated withanhydrous hydrogen chloride gas (110 g) over 1.5 hours. This solution isstirred a room temperature for 64 hours and the resulting solidscollected and washed with 500 mL diethyl ether and 2×1000 mL of ethylacetate. The remaining solids (60.4 g) are dissolved in 1200 mL of waterand the residual solids filtered. To the filtrate is added a solution ofsodium hydroxide (12.57 g) in 150 mL water. The resulting white solid isfiltered and washed with water to afford ethyl4-hydroxybenzenecarboximidoate.

A stirred solution of ethyl 4-hydroxybenzenecarboximidoate (32.0 g, 194mmol) in 250 mL anhydrous N,N-dimethylformamide is treated with cesiumcarbonate (75.7 g, 232 mmol) and 1,5-dibromopentane (89.1 g, 387 mmol)and heated at 70° C. for 1.5 hours. After cooling to room temperature,the reaction is filtered and the resulting filtrate concentrated invacuo (<1 mtorr) to afford a yellow oil (85.7 g). This material ispurified by chromatography on silica gel (850 g) with 10-60% ethylacetate/hexanes as the eluent to afford ethyl4-[5-bromopentoxy]benzenecarboximidoate as a colorless oil.

A stirred solution of4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzenecarboxamide (319 mg,1.27 mmol) in 3.5 mL anhydrous N,N-dimethylformamide is treated withcesium carbonate (435 mg, 1.33 mmol) and ethyl4-[5-bromopentoxy]benzenecarboximidoate (400 mg, 1.27 mmol) and heatedat 70° C. for 1.0 hours. After cooling to room temperature, the reactionis partitioned between ethyl acetate and water and the organics washedwith brine, dried over sodium sulfate and concentrated in vacuo toafford a yellow oil. This material is purified by chromatography onsilica gel (22 g) with 30-75% ethyl acetate/hexanes as the eluent toafford ethyl4-[5-[2-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless oil.

EXAMPLE 2

In a way analogously as described in examples 1, 7 and 15, the followingcompounds can be manufactured:

(a)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-diethylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N,N-diethylaminocarbonyl)phenoxy]pentoxy]benzenecarboximidoate(1.25 g) as colorless foam:

CHN calculated for C₂₄ H₃₄ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 60.94; % H:7.46; % N: 8.88; Found: % C: 61.10; % H: 7.47; % N: 8.99.

(b)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-methylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-methylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(475 mg) as white crystals, mp=105°-108° C.

(b')1-[4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxybenzoyl]piperidinemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-(1-piperidinylcarbonyl)phenoxy]pentoxy]benzenecarboximidoate(390 mg) as a colorless foam:

CHN calculated for C₂₅ H₃₄ N₃ O₄ Cl; Theory: % C: 63.08; % H: 7.20; % N:8.83; Found: % C: 63.05; % H: 6.97; % N: 8.54.

(c)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-(phenylmethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-(phenylmethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(412 mg) as a colorless foam:

CHN calculated for C₂₇ H₃₂ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 63.95; % H:6.56; % N: 8.29; Found: % C: 64.11; % H: 6.80; % N: 8.29.

(d)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-di-n-propylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N,N-dipropylaminocarbonyl]phenoxylpentoxy]benzenecarboximidoate(1.30 g) as a colorless foam:

CHN calculated for C₂₆ H₃₆ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 62.45; % H:7.65; % N: 8.40; Found: % C: 62.56; % H: 7.78; % N: 8.66.

(e)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-dimethylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N,N-dimethylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(474 mg) as a colorless foam:

CHN calculated for C₂₂ H₃₀ N₃ O₄ Cl-1.0H₂ O; Theory: % C: 58.21; % H:7.11; % N: 9.25; Found: % C: 58.35; % H: 6.82; % N: 9.64.

(f)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-methyl-N-(phenylmethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-methyl-N-(phenylmethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(550 mg) as a colorless foam:

CHN calculated for C₂₈ H₃₄ N₃ O₄ Cl-1.0H₂ O; Theory: % C: 63.45; % H:6.85; % N: 7.93; Found: % C: 63.74; % H: 6.61; % N: 7.96.

(g)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-ethylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-ethylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate (490 mg) as a colorless foam:

CHN calculated for C₂₂ H₃₀ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 59.39; % H:7.02; % N: 9.44; Found: % C: 59.58; % H: 6.92; % N: 9.46.

(h)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-(1,1-dimethylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-N-(1,1-dimethylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(530 mg) as a colorless foam:

CHN calculated for C₂₄ H₃₄ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 60.94; % H:7.46; % N: 8.88; Found: % C: 60.90; % H: 7.35; % N: 8.84.

(i)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-n-propylbenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-n-propylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(538 mg) as a colorless foam:

CHN calculated for C₂₃ H₃₂ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 60.19; % H:7.25; % N: 9.15; Found: % C: 60.27; % H: 7.14; % N: 9.09.

(j)1-[4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxybenzoyl]-2-methylpiperidinemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-(2-methyl-1-piperidinylcarbonyl)phenoxy]pentoxy]benzenecarboximidoate(573 mg) as a colorless foam:

CHN calculated for C₂₆ H₃₆ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 62.57; % H:7.47; % N: 8.42; Found: % C: 62.55; % H: 7.17; % N: 8.32.

(k)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxybenzoyl]morpholinemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[1-morpholino-carbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₄ H₃₂ N₃ O₅ Cl-0.75H₂ O; Theory: % C: 58.64; % H:6.87; % N: 8.55; Found: % C: 58.61; % H: 6.60; % N: 8.58.

(l)1-[4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxybenzoyl]-N,N-diethyl-3-piperidinecarboxamidemonohydrochloride is obtained from1-[4-[5-[4-ethoxyiminomethyl)phenoxy]pentoxy]-2-methoxybenzoyl]-N,N-diethyl-3-piperidinecarboxamide(1.00 g) as a colorless foam:

CHN calculated for C₃₀ H₄₂ N₄ O₅ Cl-1.0H₂ O; Theory: % C: 60.85; % H:7.49; % N: 9.46; Found: % C: 60.86; % H: 7.51; % N: 9.40.

(m)1-[4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxybenzoyl]pyrrolidinemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-(1-pyrrolidinylcarbonyl)phenoxy]pentoxy]benzenecarboximidoate(731 mg) as a colorless foam:

CHN calculated for C₂₄ H₃₄ N₃ O₄ Cl-0.75H₂ O; Theory: % C: 60.62; % H:7.10; % N: 8.84; Found: % C: 60.31; % H: 6.87; % N: 8.84.

(n) 4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-diethylbenzamidemonohydrochloride is obtained from ethyl4-[5-[4-[N,N-diethylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(678 mg) as a colorless foam:

CHN calculated for C₂₃ H₃₂ N₃ O₃ Cl-0.75H₂ O; Theory: % C: 61.73; % H:7.55; % N: 9.39; Found: % C: 61.69; % H: 7.29; % N: 9.29.

(o) 3-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-diethylbenzamidemonohydrochloride (327 mg) is obtained from ethyl3-[5-[4-[N,N-diethylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(475 mg) as a colorless foam:

CHN calculated for C₂₃ H₃₂ N₃ O₃ Cl-1.25H₂ O; Theory: % C: 60.52; % H:7.62; % N: 9.20; Found: % C: 60.71; % H: 7.31; % N: 9.14.

(p) 2-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-diethylbenzamidemonohydrochloride is obtained from ethyl2-[5-[4-[N,N-diethylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(278 mg) as a colorless foam:

CHN calculated for C₂₃ H₃₂ N₃ O₃ Cl-1.25H₂ O; Theory: % C: 60.52; % H:7.62; % N: 9.20; Found: % C: 60.51; % H: 7.18; % N: 9.36.

(q)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-dicyclohexyl-3-methoxybenzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N,N-dicyclohexylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(663 mg) as a colorless foam:

CHN calculated for C₃₂ H₄₆ N₃ O₄ Cl-0.75H₂ O; Theory: % C: 65.74; % H:8.02; % N: 7.19; Found: % C: 65.83; % H: 7.93; % N: 7.18.

(r)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-(1-methylethyl)-N-(phenylmethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[2-methoxy-4-[N-(1-methylethyl)-N-(phenylmethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(483 mg) as a colorless foam:

CHN calculated for C₃₀ H₃₈ N₃ O₄ Cl-0.75H₂ O; Theory: % C: 65.09; % H:7.19; % N: 7.59; Found: % C: 65.08; % H: 6.90; % N: 7.64.

(s)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N-cyclohexyl-N-(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3-methoxy-4-[N-cyclohexyl-N-(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(727 mg) as a colorless foam:

CHN calculated for C₂₉ H₄₂ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 64.36; % H:8.01; % N: 7.76; Found: % C: 64.44; % H: 7.80; % N: 7.77.

(t)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate(419 mg) as a colorless foam:

CHN calculated for C₂₅ H₃₆ N₃ O₃ Cl-1.0H₂ O; Theory: % C: 62.55; % H:7.97; % N: 8.75; Found: % C: 62.20; % H: 7.57; % N: 8.68.

(u)4-[5-[4-(aminoiminomethyl)-3-methoxyphenoxy]pentoxy]-N,N-bis(1-methylethyl)benzamideis obtained from ethyl4-[5-[4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]-2-methoxybenzenecarboximidoate(1.00 g) as a colorless foam:

CHN calculated for C₂₆ H₃₇ N₃ O₄ Cl; Theory: % C: 68.54; % H: 8.18; % N:9.22; Found: % C: 68.18; % H: 7.82; % N: 8.82.

(v) 4-[5-[4-(Aminoiminomethyl)phenoxy]pentoxy]-N-methyl-N-phenylbenzamide monohydrochloride is obtained from ethyl4-[5-[4-[N-methyl-N-phenylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₆ H₃₀ N₃ O₃ Cl-0.75H₂ O; Theory: % C: 64.86; % H:6.59; % N: 8.73 Found: % C: 65.02; % H: 6.36; % N: 8.80.

(w)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N-(1-methylethyl)-N-phenylbenzamidemonomethanesulfonate is obtained from ethyl4-[5-[4-[N-(1-methylethyl)-N-phenylaminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₉ H₃₇ N₃ SO₆ ; Theory: % C: 62.68; % H: 6.71; % N:7.56; Found: % C: 62.64; % H: 6.68; % N: 7.67.

(x)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-chloro-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3-chloro-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam, m.p. 125°-128° C.

CHN calculated for C₂₅ H₃₅ N₃ O₃ Cl₂ -0.5H₂ O; Theory: % C: 59.57; % H:7.28; % N: 8.01; Found: % C: 59.40; % H: 7.17; % N: 8.31.

hemifumarate salt is obtained from free base and fumaric acid

CHN calculated for C₅₄ H₇₂ N₆ O₁₀ Cl₂ ; Theory: % C: 62.60; % H: 7.00; %N: 8.11; Found: % C: 62.36; % H: 7.08; % N: 8.02;

(L)-tartrate salt is obtained from free base and (L)-tartaric acid

CHN calculated for C₂₉ H₄₀ N₃ O₉ Cl; Theory: % C: 57.10; % H: 6.61; % N:6.89; Found: % C: 57.19; % H; 6.78; % N: 6.83.

(y)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-methyl-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3-methyl-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₀ H₃₇ N₃ O₃ -1.0H₂ O; Theory: % C: 63.20; % H:8.16; % N: 8.50; Found: % C: 63.59; % H: 8.18; % N: 8.19.

(z)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam, m.p. 130°-134° C.

CHN calculated for C₂₆ H₃₈ N₃ O₄ Cl-0.5H₂ O; Theory: % C: 62.32; % H:7.84; % N: 8.38; Found: % C: 61.94; % H: 7.73; % N: 7.90.

(aa)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2,6-dichloro-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3,5-dichloro-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₅ H₃₄ N₃ O₃ Cl₃ -0.5H₂ O; Theory: % C: 55.61; % H:6.53; % N: 7.78; Found: % C: 55.81; % H: 6.39; % N: 7.64.

(bb)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2,6-dimethyl-N,N-bis(1-methylethyl)benzamidemonohydrochloride is obtained from ethyl4-[5-[3,5-dimethyl-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₇ H₄₀ N₃ O₃ Cl-1.0H₂ O; Theory: % C: 63.82; % H:8.33; % N: 8.26; Found: % C: 63.82; % H: 7.82; % N: 7.99.

(cc)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3,5-dibromo-N,N-bis(1-methylethyl)benzamidemonomethanesulfonate is obtained from ethyl4-[5-[2,6-dibromo-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₆ H₃₇ N₃ O₆ SBr₂ ; Theory: % C: 45.96; % H: 5.49; %N: 6.18; Found: % C: 45.86; % H: 5.53; % N: 6.10.

(dd)4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethylbenzamide monohydrochloride is obtained from ethyl4-[5-[3-hydroxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoateas a colorless foam:

CHN calculated for C₂₆ H₃₆ N₃ O₄ Cl-1.0H₂ O; Theory: % C: 60.53; % H:7.72; % N: 8.47; Found: % C: 60.57; % H: 7.31; % N: 8.06.

(ee)3-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-4-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride, m.p. 87°-90° C.

(ff)3-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-4-methoxy-N,N-diethylbenzamidemonohydrochloride, m.p. 73°-75° C.

(gg)3-[5-[4-(aminoiminomethyl)-3-chlorophenoxy]pentoxy]-N,N-bis(1-methylethyl)benzamidemonohydrochloride, m.p. 72°-76° C.

(hh)4-[5-[4-aminoiminomethyl-3-hydroxyphenoxy]-N,N-bis-(1-methylethyl)benzamidehydrochloride.

(ii)4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-chloro-N-phenyl-N-(1-methylethyl)benzamidehydrochloride, m.p. 110°-112° C. (d);

(jj)4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-fluoro-N,N-bis(1-methylethyl)benzamide maleate, m.p. 160°-161° C.

EXAMPLE 3

A stirred, 0° C. solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (1.9 g, 3.86 mmol) in 20 mL water is treated with 20mL of 1.0N aqueous sodium hydroxide. The solution is extractedsequentially with four 50 mL portions of dichloromethane. The combinedorganic solution is washed with brine, dried over sodium sulfate andconcentrated to give 4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (1.75 g) as acolorless foam. A portion of this material (500 mg, 1.1 mmol) isdissolved in 1 mL ethanol and treated dropwise with a solution of maleicacid (127 mg) in 1 mL ethanol. Diethyl ether (10 mL) is added slowlydropwise to induce crystallization. The crystalline product is collectedby filtration, washed with ether and dried to give4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1), mp=145°-146° C.

CHN calculated for C₃₀ H₄₁ N₃ O₈ ; Theory: % C: 63.03; % H: 7.23; % N:7.35; Found: % C: 62.97; % H: 7.04; % N: 7.29.

EXAMPLE 4

In a way analogously as described in example 3, the following compoundscan be manufactured:

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonomethanesulfonate is obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(500 mg) and methanesulfonic acid; mp=122°-123° C.

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemono-2-hydroxyethanesulfonate is obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(500 mg) and ammonium 2-hydroxyethanesulfonate; mp=118°-120° C.

EXAMPLE 5

A stirred, 0° C. solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (200 mg) in 4.0 mL anhydrous methylene chloride istreated sequentially with triethylamine (0.068 mL, 0.48 mmol) and methylchloroformate (39 mg). The solution is stirred 30 minutes, concentratedin vacuo and the resulting solids are partitioned between ethyl acetateand water. The organic layer is washed with water and brine, dried oversodium sulfate and concentrated. The resulting material is purified bychromatography on silica gel (15 g) with 70-100% ethyl acetate/hexanesas the eluent to afford4-[5-[4-[amino(methoxycarbonylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide##STR16## (i-Prop=isopropyl) as a colorless foam:

CHN calculated for C₂₈ H₃₉ N₃ O₆ ; Theory: % C: 65.48; % H: 7.65; % N:8.18; Found: % C: 65.46; % H: 7.65; % N: 8.05.

EXAMPLE 6

In a way analogously as described in example 5, the following compoundscan be prepared:

4-[5-[4-[amino(phenylmethoxycarbonylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (200 mg) and benzyl chloroformate (73 mg) as acolorless foam:

CHN calculated for C₃₄ H₄₃ N₃ O₆ -0.5H₂ O; Theory: % C: 68.21; % H:7.41; % N: 7.02; Found: % C: 68.14; % H: 7.26; % N: 6.85.

4-[5-[4-[(benzoylimino)aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (200 mg) and benzoyl chloride (61 mg) as a colorlessfoam:

CHN calculated for C₃₃ H₄₁ N₃ O₅ ; Theory: % C: 70.82; % H: 7.38; % N:7.51 Found: % C: 71.11; % H: 7.65; % N: 7.06.

4-[5-[4-[amino(1-oxo-3-phenyl-2-propenylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (400 mg) and cinnamoyl chloride (142 mg) as acolorless foam:

CHN calculated for C₃₅ H₄₃ N₃ O₅ ; Theory: % C: 71.77; % H: 7.40; % N:7.17; Found: % C: 71.95; % H: 7.60; % N: 6.91.

4-[5-[4-[amino[[[2-(1-methylethyl)-5-methylcyclohexyl]oxycarbonyl]imino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and L-menthol chloroformate (140 mg) as acolorless foam:

CHN calculated for C₃₇ H₅₅ N₃ O₆ ; Theory: % C: 69.67; % H: 8.69; % N:6.59; Found: % C: 70.35; % H: 8.38; % N: 6.18.

4-[5-[4-[amino[octyloxycarbonyl]imino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and octyl chloroformate (123 mg) as acolorless foam:

CHN calculated for C₃₅ H₅₃ N₃ O₆ ; Theory: % C: 68.71; % H: 8.73; % N:6.87; Found: % C: 68.61; % H: 8.50; % N: 6.39.

4-[5-[4-[[[9H-fluoren-9-yl)methoxycarbonyl]imino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and 9-fluorenylmethyl chloroformate (166 mg)as a colorless foam:

CHN calculated for C₄₁ H₄₇ N₃ O₆ ; Theory: % C: 72.65; % H: 6.99; % N:6.20; Found: % C: 72.40; % H: 7.09; % N: 5.93.

4-[5-[4-[amino[(methylsulfonyl)imino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and methane sulfonyl chloride (73 mg) as acolorless foam:

CHN calculated for C₂₇ H₃₉ N₃ O₆ S; Theory: % C: 60.77; % H: 7.37; % N:7.87; Found: % C: 60.85; % H: 7.55; % N: 7.66.

4-[5-[4-[amino[(phenylsulfonyl)imino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and benzenesulfonyl chloride as a colorlessfoam:

CHN calculated for C₃₂ H₄₁ N₃ O₆ S; Theory: % C: 64.51; % H: 6.94; % N:7.05; Found: % C: 64.73; % H: 7.17; % N: 6.86.

4-[5-[4-[amino[octyloxycarbonyl]imino]methyl]phenoxy]pentoxy]-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N,N-bis(1-methylethyl)benzamidemonohydrochloride (250 mg) and octyl chloroformate (103 mg) as acolorless foam:

CHN calculated for C₃₄ H₅₁ N₃ O₅ ; Theory: % C: 70.19; % H: 8.84; % N:7.72; Found: % C: 70.28; % H: 8.82; % N: 7.05.

4-[5-[4-[[[2-(dimethylamino)ethyl]methylimino]carbonyl]imino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidedihydrochloride is obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(455 mg) and phenyl [2-(dimethylamino)ethyl]methylcarbamate (450 mg) asa colorless foam:

CHN calculated for C₃₂ H₅₁ N₅ O₅ Cl₂ -1.0H₂ O; Theory: % C: 56.97; % H:7.91; % N: 10.38; Found: % C: 56.64; % H: 7.83; % N: 10.10.

4-[5-[4-[[(1,1-dimethylethoxy)carbonylimino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride and t-butoxycarbonyl (BOC) anhydride, as a colorlessfoam:

CHN calculated for C₃₁ H₄₅ N₃ O₆ -0.5H₂ O; Theory: % C: 65.93; % H:8.21; % N: 7.44; Found: % C: 66.26; % H: 8.29; % N: 7.44.

4-[5-[4-[[2,2-dimethyl-1-oxopropyl)imino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)-phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride and pivaloyl chloride as a colorless foam:

CHN calculated for C₃₁ H₄₅ N₃ O₅ -0.5H₂ O; Theory: % C: 68.99; % H:8.40; % N: 7.79; Found: % C: 68.89; % H: 8.43; % N: 7.55.

4-[5-[4-[(1-oxobutylimino)aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride and butyryl chloride as a colorless foam:

CHN calculated for C₃₀ H₄₃ N₃ O₅ ; Theory: % C: 68.54; % H: 8.25; % N:7.99; Found: % C: 68.52; % H: 8.09; % N: 7.68.

4-[5-[4-[[(1-methylethoxycarbonyl)-imino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride and isopropyl chloroformate as a colorless foam:

CHN calculated for C₃₀ H₄₃ N₃ O₆ ; Theory: % C: 66.52; % H: 8.00; % N:7.76; Found: % C: 66.15; % H: 7.80; % N: 7.48.

4-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride and acetyl chloride as a colorless foam:

CHN calculated for C₂₈ H₃₉ N₃ O₅ ; Theory: % C: 67.58; % H: 7.90; % N:8.44; Found: % C: 67.46; % H: 8.10; % N: 8.10.

EXAMPLE 7

4-[5-[4-(Aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(3.65 kg, 8.01 mole) is dissolved in acetonitrile (29.2 L) with warmingto 60° C. and filtered gravimetrically into a 20 gallon reactor. Theproduct crystallizes out and is rewarmed to effect solution. A hotfiltered solution of maleic acid (930 g, 8.02 mole) in acetonitrile (9.2L) is added rapidly and an exotherm occurs to 63° C. A solidcrystallizes and then redissolves. The reaction mixture is stirred to55° C. at which point crystallization begins. The hot water bath isreplaced with an ice bath and the suspension cooled to 10° C. andfiltered. A second reaction mixture of the same size is runsimultaneously and filtered along with the first reaction mixture. Theproduct is washed with acetonitrile (4×2L) and dried in vacuo (80° C., 3mm Hg) at for 24 hours and at 83° C. for another 24 hours to give thecrude product (HPLC 99.3%).

Acetonitrile (43.9 L), water (4.39 L) and4-[5-[4-(aminoiminomethyl)-phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1) (8,780 g) are combined in a 20 gallon reactorand heated to 60° C. to effect a solution. Charcoal G-60 (440 g) isadded and the reaction mixture stirred 1/2 hour at 60° C. and filteredgravimetrically through a heated funnel into another 20 gallon reactor.The product is allowed to crystallize at ambient temperature for 66hours, stirred gently overnight 15 hours and filtered, washed with water(3×4 L) and dried in vacuo (85° C., 3 mm Hg) for 24 hours under anitrogen sweep to give the pure product,4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1), mp=164°-166° C.

The starting material can be prepared, for example, as follows:

To a solution of 1-bromo-5-chloropentane (3794 g, 20.45 mol) inacetonitrile (38 L) is added 4-cyanophenol (2437 g, 20.45 mol) andpowdered powdered potassium carbonate (2827 g, 20.45 mol). Thissuspension is heated with stirring under nitrogen at 96° C. bathtemperature (82° C.-internal) for 20 hours. Additional powderedpotassium carbonate (2827 g, 20.45 mol.) is then added to the hotreaction mixture followed by potassium iodide (3397 g, 20.45 mol) andmethyl vanillate (3725 g, 20.45 mol). The reaction mixture is heatedunder nitrogen for another 3 days until TLC shows no intermediate chlorocompound present. The bath is removed and stirring stopped. The reactionmixture is filtered hot through a filter crock and into another 20gallon reactor. The filtrate is stirred and cooled with an ice bath to10° C. for 3 hours and the product filtered, washed with diethyl ether(4×1 L) and dried in vacuo (50° C., 3 mm Hg) to give methyl4-[5-(4-cyanophenoxy)-pentoxy]-3-methoxybenzoate, mp 105°-107° C., HPLCindicating a purity of 99.8%.

Methyl 4-[5-(4-cyanophenoxy)-pentoxy]-3-methoxybenzoate (3600 g, 9.74mol) is dissolved in tetrahydrofuran (36 L) with warming to 30° C. Thesolution is then cooled to 20° C. and a solution of tetrabutylammoniumhydroxide (40% in water, 7.1 L, 1.64 m) is added over 20 minutes. Thereaction mixture is then stirred at an internal temperature of 25° C.for 7 hours and overnight at room temperature (23° C.). After cooling to10° C. with an ice bath, hydrochloric acid (1.0N, 14.4 L) is added over1 hour. After stirring and cooling to 10° C. for three hours, theproduct is filtered, washed with water (24 L) and dried in vacuo (76°C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoicacid, mp 159°-161° C. HPLC indicates 99.1% purity. A second crop of acidis obtained from the filtrates after diluting further with water (20 L).The product is filtered, washed with water (4×3 L) and dried in vacuo togive 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid, mp 158°-160°C., (HPLC indicates 98.3% purity).

4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol)is suspended in dichloromethane (36 L) and to this is added thionylchloride (1345 g, 11.30 mol) dropwise over 20 minutes followed bydimethylformamide (74.4 g, 10.0 mol). The reaction mixture is stirred atroom temperature for 21 hours; after 6 hours a complete solution isobtained. The solution is concentrated in vacuo (50° C., 3 mm Hg) togive 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid,which is then redissolved in dichloromethane (36 L) without furtherpurification and cooled to 5° C. with an ice bath. Diisopropylamine(3077 g, 30.40 mol) is added dropwise over a period of 1 hour. Thereaction mixture is stirred at 20° C. for 3 hours and then,N,N-dimethylethylenediamine (80.3 g, 0.91 mol) is added. The reaction isfollowed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no morebyproduct (bis-anhydride of4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid) is detected. Thereaction mixture is then stirred overnight at room temperature. Water(18 L) is added, stirred and the layers separated. The organic layer iswashed with hydrochloric acid (1.0N, 23 L), water (18 L), ammoniumhydroxide (0.5N, 2×23 L), water (18 L) and brine solution (18 L). Theseparated dichloromethane solution is dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamideas a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warmingand to the solution is added water (8.6 L). The product is allowed tocrystallize overnight in an ice bath. The product is filtered, washedwith EtOH/H₂ O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamide,mp 90°-92° C. HPLC indicates a purity of >99.7%.

Ethanol (2B,6.0 L) is cooled in an ice bath to 0° C. and saturated withanhydrous hydrogen chloride over a period of 71/2 hours. The solution isleft in the ice bath overnight and the hydrogen chloride addition iscontinued an additional hour at 0° C.4-[5-(4-Cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamide(4200 g, 9.57 mole) is added rapidly over 30 minutes and an exothermraises the reaction mixture temperature to 10° C. Hydrogen chlorideaddition is continued for 6 hours and the purple solution stirredovernight at 20° C. The reaction mixture is followed by TLC (ethylacetate/hexane, 2:1) using silica plates. A total of 4-5 days isrequired for completion of this reaction with periodic resaturation withhydrogen chloride. The thick purple solution is transferred into a 20gallon reactor and triturated with anhydrous diethyl ether (2×30 L),removing the ether solution after each wash. The reactor is put undervacuum (3 mm Hg) for 0.5 hour to dispel most of the hydrogen chlorideleaving ethyl4-[5-[3-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoatemonohydrochloride as a thick purple oil.

Ethanol 2 B (42 L) is added to the reactor and the ethyl4-[5-[3-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-pentoxy]benzenecarboximidoatemonohydrochloride is dissolved. The solution is cooled to 5° C. andanhydrous ammonia is bubbled into the solution for 7.5 hours untilsaturation is obtained. After stirring overnight in the ice bath, andammonia addition is continued another 7.5 hours at 5° C. The reactionmixture is followed by TLC (CH₂ Cl₂ /MeOH, 9:1) using silica plates. Atotal of four days is required for completion of reaction with periodicresaturation with ammonia gas. The reaction mixture is filtered and thefiltrate divided into two equal portions. Concentration in vacuo (55°C., 3 mm Hg) gives an oily viscous suspension which is charged into a 20gallon reactor. This is admixed with hydrochloric acid (12N, 560 ml),diluted with water (44 L). At this point, the compound dissolves (pH is1.62). The solution is washed with diethyl ether (3×18 L), and the pHadjusted to 12.6 with a 6N sodium hydroxide solution (3.0 L). The oilysuspension crystallizes after stirring overnight at 20° C. The productis filtered, washed with water (5×4 L) and dried in vacuo (60° C. 3 mmHg) to give the product. The second half of the reaction mixture isworked up in a similar manner to give4o[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamideis obtained, mp 112°-114° C. HPLC indicates a purity of 98.5%.

EXAMPLE 8

A stirred, 0° C. solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (200 mg, 0.41 mmol) in 4.0 mL anhydrous methylenechloride is treated sequentially with triethylamine (0.068 mL, 0.48mmol) and methyl isocyanate (0.030 mL, 0.49 mmol). The solution isstirred 30 minutes, concentrated in vacuo and the resulting solids arepartitioned between ethyl acetate and water. The organic layer is washedwith water and brine, dried over sodium sulfate and concentrated. Theresulting material is purified by chromatography on silica gel (15 g)with 70-100% ethyl acetate/hexanes as the eluent to afford4-[5-[4-[amino(methylaminocarbonylimino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideas a colorless foam:

CHN calculated for C₂₈ H₄₀ N₄ O₅ ; Theory: % C: 65.60; % H: 7.87; % N:10.93; Found: % C: 65.79; % H: 7.61; % N: 10.90.

EXAMPLE 9

In a way analogously as described, for example, in example 8, thefollowing compounds can be manufactured:

4-[5-[4-[Amino[(3,4-dimethoxyphenyl)carbonylimino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (400 mg) and 3,4-dimethoxybenzoyl chloride (170 mg) asa colorless foam:

CHN calculated for C₃₅ H₄₅ N₃ O₇ ; Theory: % C: 67.83; % H: 7.32; % N:6.78; Found: % C: 68.19; % H: 7.55; % N: 6.23.

4-[5-[4-[Amino[[[(1-methylethyl)amino]carbonyl]imino)methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and isopropyl isocyanate (54 mg) as acolorless foam:

CHN calculated for C₃₀ H₄₄ N₄ O₅ ; Theory: % C: 66.64; % H: 8.20; % N:10.36; Found: % C: 66.94; % H: 8.09; % N: 9.99.

4-[5-[4-[(Ethylamino)carbonyl]imino]aminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and ethyl isocyanate (45 mg) as a colorlessfoam:

CHN calculated for C₂₉ H₄₂ N₄ O₅ ; Theory: % C: 66.13; % H: 8.0; % N:10.64; Found: % C: 66.35; % H: 7.96; % N: 10.25.

4-[5-[4-[Amino[[(phenylamino)carbonyl]imino]methyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(240 mg) is obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (300 mg) and phenyl isocyanate (76 mg) as a colorlessfoam:

CHN calculated for C₃₃ H₄₂ N₄ O₅ ; Theory: % C: 68.97; % H: 7.37; % N:9.75; Found: % C: 69.20; % H: 7.75; % N: 9.37.

EXAMPLE 10

In a way analogously as described, for example, in one of the preceedingexamples, the following compounds can be manufactured:

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-N-ethyl-N-phenylbenzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2,6-dimethoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3,5-dimethoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2,3-dimethoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3,5-dichloro-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-methoxy-6-methyl-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-chloro-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-bromo-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

5-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

5-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-bromo-N,N-bis(1-methylethyl)benzamidemonohydrochloride;

4-[5-[4-[(3-pyridylcarbonylamino)iminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide;

4-[5-[4-[(4-pyridylcarbonylamino)iminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide;

4-[5-[4-[1-imidazolylcarbonylamino)iminomethyl]phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide.

4-[5-[(4-aminoiminomethyl)phenoxy]pentoxy]-N-(1-methylethyl)-N-(2-pyridyl)-benzamidedi-methanesulfonate, m.p. 148°-151°.

EXAMPLE 11

A stirred solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(40.0 g, 87.7 mmol) in 500 mL anhydrous methylene chloride is treatedwith phenyl acetate (11.1 mL, 87.7 mmol). The solution is stirred 3hours, concentrated in vacuo and the resulting liquid is purified bychromatography on silica gel (850 g) with 30% ethyl acetate/hexane asthe eluent to afford4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideas a colorless foam:

CHN calculated for C₂₈ H₃₉ N₃ O₅ ; Theory: % C: 67.58; % H: 7.90; % N:8.44; Found: % C: 67.32; % H: 8.29; % N: 8.28.

EXAMPLE 12

A stirred solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (220 mg, 0.46 mmol) in 10 mL anhydrous methylenechloride is treated with phenyl acetate (73 uL, 0.51 mmol) andtriethylamine (73 uL, 0.51 mmol). The solution is stirred overnight,concentrated in vacuo and the resulting liquid is purified bychromatography on silica gel (15 g) with 80°-100% ethyl acetate/hexaneas the eluent to afford4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamideas a colorless foam:

CHN calculated for C₂₇ H₃₇ N₃ O₅ -0.5H₂ O; Theory: % C: 65.83; % H:7.78; % N: 8,53; Found: % C: 65.58; % H: 7.63; % N: 8,16.

EXAMPLE 13

In a way analogously as described in the previous two examples, thefollowing compounds can be prepared:

(a)4-[5-[4-[amino(propanoylimino)methyl]phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideas colorless foam:

CHN calculated for C₂₉ H₄₁ N₃ O₅ ; Theory: % C: 68.08; % H: 8.08; % N:8,21; Found: % C: 67.85; % H: 8.35; % N: 7.95.

(b)4-[5-[4-(Acetyliminoaminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamidemonohydrochloride as colorless foam:

CHN calculated for C₂₇ H₃₇ N₃ O₄ ; Theory: % C: 69.30; % H: 7.86; % N:8,60; Found: % C: 69.35; % H: 7.98; % N: 8.99.

(c)4-[5-[4-[Amino(propanoylimino)methyl]phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride as colorless foam:

CHN calculated for C₂₈ H₃₉ N₃ O₅ -0.5H₂ O; Theory: % C: 66.38; % H:7.96; % N: 8.29; Found: % C: 66.67; % H: 7.84; % N: 8,03.

(d)4-[5-[4-[amino(butyrylimino)methyl]phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride as colorless foam:

CHN calculated for C₂₉ H₄₁ N₃ O₅ -1.0H₂ O; Theory: % C: 65.76; % H:8.18; % N: 7.93; Found: % C: 65.92; % H: 7.98; % N: 7.69.

(e)4-[5-[4-[Amino(propanoylimino)methyl]phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamidehydrochloride as a colorless solid:

CHN calculated for C₂₈ H₃₉ N₃ O₄ ; Theory: % C: 69.83; % H: 8.16; % N:8.72; Found: % C: 70.05; % H: 8.23; % N: 8.64.

(f)4-[5-[4-[(Acetylimino)aminomethyl]phenoxy]pentyloxy]-2-chloro-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-chloro-N,N-bis(1-methyethyl)benzamide,m.p. 59°-61° C.:

CHN calculated for C₂₇ H₃₆ N₃ O₄ Cl; Theory: % C: 64.60; % H: 7.23; % N:8.37; Found: % C: 64.26; % H: 6.95; % N: 7.91.

(g)4-[5-[4-[(Propionylimino)aminomethyl]phenoxy]pentyloxy]-2-chloro-N,N-bis(1-methylethyl)benzamideis obtained from4-[5-(aminoiminomethyl)phenoxy]pentyloxy]-2-chloro-N,N-bis(1-methylethyl)benzamide,m.p. 59°-60° C.:

CHN calculated for C₂₈ H₃₈ N₃ O₄ Cl; Theory: % C: 65.17; % H: 7.42; % N:8.14; Found: % C: 64.94; % H: 7.24; % N: 7.90.

(h)4-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-chloro-N-phenyl-N-(1-methylethyl)benzamideis obtained from4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-chloro-N-phenyl-No(1-methylethyl)benzamide,m.p. 58°-60° C.:

CHN calculated for C₃₁ H₃₆ N₃ O₄ Cl.1.0H₂ O; Theory: % C: 65.54; % H:6.74; % N: 7.40; Found: % C: 65.59; % H: 6.55; % N: 7.77.

EXAMPLE 14

A stirred solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(3.0 g, 7.06 mmol) in 15 mL of dichloromethane is treated with1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.67 g,8.47 mmol), hydroxybenzotriazole (1.14 g, 8.47 mmol), and2-(benzoyloxymethyl)benzoic acid (1.81 g, 7.06 mmol) and stirred at roomtemperature over 2 hours. The reaction is concentrated in vacuo andpurified by chromatography on silica gel (50 g) with 60% ethylacetate/hexane as the eluent to afford4-[5-[4-amino[2-(benzoyloxymethyl)benzoyl]iminomethyl]phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamideas a colorless foam:

CHN calculated for C₄₂ H₄₇ N₃ O₇ ; Theory: % C: 70.92; % H: 6.82; % N:6.06; Found: % C: 70.77; % H: 6.74; % N: 5.83.

EXAMPLE 15

Amberlite IRA-400 (OH) ion-exchange resin (55.5 g) is added in oneportion to a stirred ethanol (120 mL)/methanol (30 mL) solution of4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride (20 g). After stirring for 20 hours, the resin isremoved by filtration. The mother liquor is concentrated at reducedpressure to afford4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide.

The starting material can be prepared as follows:

Acetic anhydride (72.9 g, 67.4 mL) is added under nitrogen at roomtemperature to 4-hydroxy-3-methoxybenzoic acid (97.7 g) in xylenes (817g, 950 mL) while stirring. The stirred mixture is heated to 115°-125° C.and heated at 120°-125° C. for 4 to 20 hours under nitrogen. Part of theliquid is then removed by distillation at about 150° bath temperature toa volume of about 700 ml and the mixture is cooled to room temperatureto obtain a slurry of 4-acetoxy-3-methoxybenzoic acid which is againdiluted with additional xylenes (224 g, 226 mL). N,N-dimethylformamide(DMF, 1.9 g, 2.0 mL) is added followed by dropwise addition, over 2.5hours, of oxalyl chloride (90.6 g, 62.2 mL). The reaction mixture isstirred at room temperature for 24 hours to obtain a solution of4-acetoxy-3-methoxybenzoyl chloride which is used as such in the nextstep. The xylenes solution is cooled to -14° to -20° C. with a brinesolution and diisopropylamine (169 g, 234 mL) is added dropwise over a45 minute period, at a rate so that the temperature does not exceed 0°C. The reaction mixture is allowed to warm to room temperature and isstirred at room temperatue (17°-20° C.) for 21 hours. The resultingslurry is filtered under vacuum, and the filter cake is further slurriedwith xylenes (430 mL) and filtered.

The combined filtrate (about 1260 mL), containing4-acetoxy-3-methoxy-N,N-bis(1-methylethyl)-benzamide, is treated at roomtemperature under nitrogen while stirring with 2-aminoethanol (43.1 g,42.6 mL) added dropwise over a 5 minute period. The reaction mixture isthen heated at 78°-85° for 5 hours. The heat source is removed and water(400 mL) is added slowly over a period of 30 minutes. The stirred slurryis cooled to room temperature and stirring at room temperature iscontinued for 16 hours. The suspension is cooled to 5° C. and filtered.The resulting solid is washed with xylenes and dried in a vacuum oven at40°-45° C. for 48 hours to obtain4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzamide; ¹ H-NMR (CDCl₃):δ1.10-1.50 (m, 12H), 3.62-3.80 (m, 2H), 3.82 (s, 3H), 6.42-6.70 (m, 1H),6.72-6.88 (m, 3H).

1-Bromo-5-chloropentane (84.7 g, 60.2 mL) is added to a stirred slurryof 4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzamide (109 g) andpowdered potassium carbonate (72.1 g) in 2-butanone (805 g, 1099 mL).The reaction mixture is heated at 80° C. for 21 hours with moderatestirring, and the slurry is filtered hot to obtain a 2-butanone solutioncontaining4-(5-chloropentyloxy)-3-methoxy-N,N-bis(1-methylethyl)benzamide. Sodiumiodide (97.8 g) is added. The mixture is heated at 80° C. for 21 hourswith moderate stirring, and filtered while hot to obtain a 2-butanonesolution of4-(5-iodopentyloxy-3-methoxy-N,N-bis(1-methylethyl)benzamide. Powderedpotassium carbonate (72.1 g) and 4-cyanophenol (67.4 g) are added. Afterthe mixture is stirred moderately for 5 minutes,tris[2-(2-methoxyethoxy)ethyl]amine (3.52 g) is added in one portion andthe resulting slurry is heated at 78°-80° C. for 21 hours with moderatestirring. The slurry is cooled to 25°-35° C. and sodium hydroxide (1N,500 mL) is added. The mixture is stirred for 10 minutes, and the aqueouslayer is then separated. The organic layer (ca. 1300 mL) is washed withsaturated sodium chloride solution (500 mL), and 940 mL of the solventis removed by distillation at 115° C. The remaining solution is cooledto 60° C., cyclohexane (1526 mL) is added over a 5 minute period,followed by antistatic agent (ASA-3, 0.17 g). The mixture is heated at76°-79° C. for 5 minutes and filtered hot under vacuum. The filtrate isheated at 76°-79° C. for 5 minutes, cooled slowly to room temperatureand stirred over the weekend. The suspension is then cooled to -8°-12°C. and stirred at this temperature for 1.5 hours. The slurry isfiltered, the collected product is washed with 2-butanone (22.2mL)/cyclohexane (178 mL), and dried at 46°-50° C. for 24 hours to yield4-[5-(4-cyanophenoxy)pentyloxy-3-methoxy-N,N-bis(1-methylethyl)benzamide.Crude product (144 g) is purified by suspending in 2-butanone (215mL)/cyclohexane (1218 mL) with antistatic agent, heating at about 80°for 5 minutes, faltering the solution while hot, cooling the filtrate toroom temperature, stirring overnight, then cooling to 8°-10° C. andstirring for 1.5 hours at 8°-10° C. The slurry is vacuum filtered, thecollected product is washed with 2-butanone/cyclohexane, and dried at46°-50° in a vacuum oven for 24 hours to obtain pure4-[5-(4-cyanophenoxy)pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide;¹ H-NMR (DMSO): δ1.10-1.50 (m, 12H), 1.50-1.65 (m, 2H), 1.75-1.85 (m,4H), 3.55-3.80 (m, 2H), 3.75 (s, 3H), 3.96 (t, J=6.3 Hz, 2H) 2H),6.75-6.85 (m, 2H), 6.92-6.98 (d, J=8.7 Hz, ¹ H), 7.06-7.12 (d, J=8.5 Hz,2H), 7.72-7.78 (d, J=8.4 Hz, 2H).

4-[5-(4-Cyanophenoxy)pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidecan be converted to4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamidemonohydrochloride similarly to corresponding steps in e.g. example 7.

EXAMPLE 16

(a) To a mixture of 5.0 g (9.2 mmol) of4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamidemonohydrochloride in 10 ml of methylene chloride is added 3.3 g (18.4mmol) of isonicotinoyl chloride hydrochloride and 5.0 ml oftriethylamine. The mixture is stirred at room temperature for 24 hoursand purified by chromatography on silica gel with 80% ethylacetate/hexane as the eluent to obtain4-[5-[4-[(isonicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamide:

CHN calculated for C₃₁ H₃₈ N₄ O₄ ; Theory: % C: 70.19; % H: 7.17; % N:10.56; Found: % C: 69.74; % H: 7.31; % N: 10.28.

Treatment with maleic acid in methanol yields maleate salt:

CHN calculated for C₃₅ H₄₂ N₄ O₈.1.0H₂ O; Theory: % C: 64.11; % H: 6.61;% N: 8.54; Found: % C: 63.96; % H: 6.77; % N: 8.34.

(b) Similarly prepared is4-[5-[4-[(nicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamide:

CHN calculated for C₃₁ H₃₈ N₄ O₄.0.5H₂ O; Theory: % C: 68.99; % H: 7.28;% N: 10.38; Found: % C: 68.65; % H: 7.00; % N: 10.07.

Treatment with maleic acid in methanol yields maleate salt:

CHN calculated for C₃₅ H₄₂ N₄ O₈.1.0H₂ O; Theory: % C: 64.11; % H: 6.61;% N: 8.54; Found: % C: 64.03; % H: 6.58; % N: 8.41.

EXAMPLE 17

a) Preparation of 10,000 tablets each containing 20 mg of the activeingredient, for example,4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1):

    ______________________________________                                        active ingredient  200.00 g                                                   Lactose            2,535.00 g                                                 Corn starch        125.00 g                                                   Polyethylene glycol 6,000                                                                        150.00 g                                                   Magnesium stearate 40.00 g                                                    Purified water     q.s.                                                       ______________________________________                                    

Procedure: All the powders are passed through a screen with openings of0.6 mm. The drug substance, lactose, magnesium stearate and haft of thestarch are mixed in a suitable mixer. The other half of the starch issuspended in 65 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 250 ml of water. The paste formedis added to the powders, which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35° C.broken on a screen with 1.2 mm openings and compressed into tablets,using concave punches uppers bisected.

Analogously tablets are prepared, containing about 10-100 mg of one ofthe other compounds disclosed and exemplified herein.

b) Preparation of 1,000 capsules each containing 40 mg of the activeingredient, for example,4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1):

    ______________________________________                                        active ingredient                                                                              40.00 g                                                      Lactose          177.00 g                                                     Modified starch  80.00 g                                                      Magnesium stearate                                                                             3.00 g                                                       ______________________________________                                    

Procedure: All the powders are passed through a screen with openings of0.6 mm. The drug substance is placed in a suitable mixer and mixed firstwith the magnesium stearate, then with the lactose and starch untilhomogenous. No. 2 hard gelatin capsules are filled with 300 mg of saidmixture each, using a capsule filling machine.

Analogously capsules are prepared, containing about 10-100 mg of theother compounds disclosed and exemplified herein.

(c) Preparation of 3000 capsules each containing 25 mg of the activeingredient, for example,4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1):

    ______________________________________                                        Active ingredient   75.00 g                                                   Lactose             750.00 g                                                  Avicel PH 102       300.00 g                                                  (microcystalline cellulose)                                                   Polyplasdone XL     30.00 g                                                   (polyvinylpyrrolidone)                                                        Purified water      q.s.                                                      Magnesium stearate  9.0 g                                                     ______________________________________                                    

The active ingredient is passed through a No. 30 hand screen.

The active ingredient, lactose, Avicel PH 102 and Polyplasdone XL areblended for 15 minutes in a mixer. The blend is granulated withsufficient water (about 500 mL), dried in an oven at 35° C. overnight,and passed through a No. 20 screen.

Magnesium stearate is passed through a No. 20 screen, added to thegranulation mixture, and the mixture is blended for 5 minutes in amixer. The blend is encapsulated in No. 0 hard gelatin capsules eachcontaining an amount of the blend equivalent to 25 mg of the activeingredient.

What is claimed is:
 1. A compound of the formula ##STR17## wherein theC(═NH)--NHR₃ group may be in tautomeric or isomeric form,R₁ is aminowhich is mono- or disubstituted by a substituent selected from analiphatic hydrocarbon radical, an araliphatic hydrocarbon radical, anaromatic radical, and a cycloaliphatic hydrocarbon radical, or is aminowhich is disubstituted by a divalent aliphatic hydrocarbon radical or asaid radical interrupted by oxygen; R₂ is hydrogen, halogen,trifluoromethyl, an aliphatic hydrocarbon radical, or is hydroxy whichis etherified by an aliphatic alcohol, araliphatic alcohol, or aromaticalcohol or which is esterified by an aliphatic or araliphatic carboxylicacid; or R₂ is hydroxy; R₃ is hydrogen or an acyl radical which isderived from an organic carbonic acid, an organic carboxylic acid, asulfonic acid, or a carbamic acid; X₁ and X₃, independently of oneanother, are oxygen (--O--) or sulphur (--S--); and X₂ is a divalentaliphatic hydrocarbon radical which may be interrupted by an aromaticradical; wherein the phenyl rings of formula I may be, independently ofone another, further substituted by one or more substituents selectedfrom halogen, trifluoromethyl, an aliphatic hydrocarbon radical,hydroxy, and hydroxy which is etherified by an aliphatic alcohol orwhich is esterified by an aliphatic or araliphatic carboxylic acid;wherein aryl in the above definitions may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid; wherein acycloaliphatic hydrocarbon radical may be substituted by an aliphaticradical; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 whereinR₁ is amino which is mono- or disubstitutedby a substituent selected from lower alkyl, lower alkenyl, loweralkynyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl,phenyl, naphthyl, indanyl, fluorenyl, cycloalkyl, and cycloalkenyl,cycloalkyl and cycloalkenyl each being unsubstituted or mono- orpolysubstituted by lower alkyl, or is amino which is disubstituted bylower alkylene; R₂ is hydrogen, halogen, trifluoromethyl, lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy,phenyl-lower alkoxy, phenoxy, lower alkanoyloxy, lower alkenoyloxy, orphenyl-lower alkanoyloxy; or R₂ is hydroxy; R₃ is hydrogen,alkoxycarbonyl or alkenyloxycarbonyl, each of which is unsubstituted orsubstituted by phenyl, naphthyl, indanyl or fluorenyl, or iscycloalkoxycarbonyl being unsubstituted or mono- or polysubstituted bylower alkyl, or is lower alkanoyl or phenyl-lower alkanoyl, or isbenzoyl, naphthtoyl, indanoyl or fluorenoyl, or is C₁ -C₇alkanesulfonyl, phenyl-C₁ -C₇ alkanesulfonyl, C₃ -C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which issubstituted by lower alkyl, phenyl-lower alkyl or phenyl; X₁ and X₃,independently of one another, are O or S; X₂ is lower alkylene, loweralkylene-phenylene-lower alkylene or lower alkylene-naphthylene-loweralkylene; wherein the phenyl rings of formula I may be, independently ofone another, substituted by one or more substituents selected fromhalogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl,hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, loweralkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy; wherein thearomatic radicals in the above definitions may be, independently of oneanother, substituted by one or more substituents selected from halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy,lower alkenoyloxy and phenyl-lower alkanoyloxy; or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 1 whereinR₁ isamino which is mono- or disubstituted by a substituent selected from C₁-C₇ -alkyl, phenyl-C₁ -C₇ -alkyl, phenyl and C₃ -C₆ -cycloalkyl, C₃ -C₆-cycloalkyl being unsubstituted or mono- or polysubstituted by C₁ -C₇-alkyl, or is amino which is disubsfituted by C₃ -C₆ -alkylene; R₂ ishydrogen, C₁ -C₇ -alkoxy or phenyl-C₁ -C₄ -alkoxy; or R₂ is hydroxy; R₃is hydrogen, C₁ -C₁₂ -alkoxy-carbonyl, C₂ -C₅ -alkanoyl, phenyl-C₂ -C₅-alkanoyl, benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁ -C₇ -alkyl, or C₁ -C₇ -alkoxy, C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₇-alkyl, or is benzoyl, naphthtoyl, indanoyl or fluorenoyl, or is C₁ -C₇alkanesulfonyl, phenyl-C₁ -C₇ alkanesulfonyl, C₃ -C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which issubstituted by C₁ -C₇ -alkyl, phenyl-C₁ -C₇ -alkyl or phenyl; X₁ and X₃each are --O--; X₂ is C₂ -C₇ -alkylene or C₂ -C₄ -alkylene-phenylene-C₂-C₄ -alkylene; wherein the phenyl tings of formula I may beunsubstituted or, furthermore, independently of one another, substitutedby one or more substituents selected from halogen, trifluoromethyl, C₁-C₇ -alkyl, and C₁ -C₇ -alkoxy; wherein phenyl in the above definitionsis unsubstituted or, furthermore, independently of one another,substituted by one or more substituents selected from halogen,trifluoromethyl, C₁ -C₇ -alkyl, and C₁ -C₇ -alkoxy; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 wherein --CO--R₁ is located in position 4 (para) of thecorresponding phenyl ting with respect to --X₁ --; R₂ -- is located inposition 2 (ortho) or 3 (meta) of the corresponding phenyl ring withrespect to --X₁ --; and --C(═NH)--NHR₃ is located in position 4 (para)of the corresponding phenyl ring with respect to --X₃ --.
 5. A compoundaccording to claim 1 of the formula IA ##STR18## wherein theC(═NH)--NHR₃ group may be in tautomeric or isomeric form,R₁ is di-C₁ -C₄-alkylamino, C₁ -C₄ alkyl-(phenyl)amino, C₁ -C₄ alkyl-(phenyl-C₁ -C₄-alkyl)-amino, di-C₃ -C₆ -cycloalkylamino which is unsubstituted orsubstituted by C₁ -C₄ -alkyl, or 1-piperidino substituted by C₁ -C₄-alkyl; R₂ is hydrogen, C₁ -C₄ -alkoxy or hydroxy; R₃ is hydrogen, C₁-C₁₂ -alkoxycarbonyl, phenyl-C₁ -C₄ -alkoxycarbonyl, C₂ -C₅ -alkanoyl,benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁ -C₄ -alkyl or by C₁ -C₄ -alkoxy, or C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₄-alkyl; X₁ and X₃ are --O--; X₂ is C₄ -C₇ -alkylene; wherein the phenylrings of formula IA may be unsubstituted or, furthermore, independentlyof one another, substituted by one or more substituents selected fromhalogen, trifluoromethyl, C₁ -C₄ -alkyl and C₁ -C₄ -alkoxy; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 of formula IB ##STR19## wherein the C(═NH)--NHR₃ group may be intautomeric or isomeric form,R₁ is di-C₁ -C₄ -alkylamino, C₁ -C₄-alkyl-(phenyl)-amino, C₁ -C₄ -alkyl-(phenyl-C₁ -C₄ -alkyl)-amino, di-C₃-C₆ -cycloalkylamino which is unsubstituted or substituted by C₁ -C₄-alkyl, or 1-piperidino substituted by C₁ -C₄ -alkyl; R₂ is hydrogen orC₁ -C₄ -alkoxy; or R₂ is hydroxy; R₃ is hydrogen, C₁ -C₁₂-alkoxycarbonyl, phenyl-C₁ -C₄ -alkoxycarbonyl, C₂ -C₅ -alkanoyl,benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁ -C₄ -alkyl or by C₁ -C₄ -alkoxy, or C₃ -C₆-cycloalkylcarbonyl which is unsubstituted or substituted by C₁ -C₄-alkyl; X₁ and X₃ are --O--; X₂ is C₄ -C₇ -alkylene; wherein the phenylrings of formula IB may be unsubstituted or, furthermore, independentlyof one another, substituted by one or more substituents selected fromhalogen, trifluoromethyl, C₁ -C₄ -alkyl, and C₁ -C₄ -alkoxy; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 6 whereinR₁ is di-C₁ -C₄ -alkylamino, C₁ -C₄ -alkyl-phenyl-amino,C₁ -C₄ -alkyl-phenyl-C₁ -C₄ -alkyl-amino, di-C₃ -C₆ -cycloalkylaminowhich is unsubstituted or substituted by C₁ -C₄ -alkyl, or 1-piperidinosubstituted by C₁ -C₄ -alkyl; R₂ is hydrogen, hydroxy or C₁ -C₄ -alkoxy;R₃ is hydrogen or C₂ -C₅ -alkanoyl; X₁ and X₃ are --O--; X₂ is C₄ -C₇-alkylene; or a pharmaceutically acceptable salt thereof.
 8. A compoundaccording to claim 6 whereinR₁ is di-C₁ -C₄ -alkylamino; R₂ is hydrogen,hydroxy or C₁ -C₄ -alkoxy; R₃ is hydrogen or C₂ -C₅ -alkanoyl; X₁ and X₃are --O--; and X₂ is C₄ -C₇ -alkylene; or a pharmaceutically acceptablesalt thereof.
 9. A compound according to claim 6 wherein R₂ is hydroxy,and X₂ is pentylene.
 10. A compound according to claim 5 which is4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-diethylbenzamideor a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 6 which is4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethylbenzamide or a pharmaceutically acceptable salt thereof.
 12. A compoundaccording to claim 6 which is4-[5-[4-(propionyliminoaminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide.13. A compound according to claim 1 which is4-[5-[4-[(isonicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1-methylethyl)-benzamideor a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1 which is4-[5-[4-[(nicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamideor a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition suitable for antagonizing LTB₄ in mammals comprising aneffective LTB₄ antagonizing amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 16. A method of antagonizing LTB₄activity in mammals which comprises administering to a mammal in needthereof an effective LTB₄ antagonizing amount of a compound according toclaim 1 in a pharmaceutically acceptable carder.